Amino thiazole compounds

ABSTRACT

The present invention relates to new 3,7-disubstituted-3-cephem-4-carboxylic acid compounds and pharmaceutically acceptable salts thereof which have antimicrobial activities and to processes for preparation thereof, to pharmaceutical compositions comprising the same, and to a method of using the same therapeutically in the treatment of infectious diseases in humans and animals. 
     This division relates to intermediate compounds, namely amino or amido-thiazolyl, substituted oxyimino disubstituted acetic acid of the formula: ##STR1## wherein R 1  is amino or a protected amino group; 
     R 2  is --CONH--R 5  or --HNCO--R 5 , 
     R 5  is aryl or heterocyclic, either of which may be substituted, and 
     A is lower alkylene, or a salt thereof.

This is a division of application Ser. No. 258,661, filed Apr. 29, 1981,now U.S. Pat. No. 4,506,076, issued 03-19-85 which in turn is a divisionof Ser. No. 56,504, filed July 11, 1979, now U.S. Pat. No. 4,288,435issued 90-08-81.

The present invention relates to new3,7-disubstituted-3-cephem-4-carboxylic acid compounds andpharmaceutically acceptable salts thereof. More particularly, it relatesto new 3,7-disubstituted-3-cephem-4-carboxylic acid compounds andpharmaceutically acceptable salts thereof which have antimicrobialactivities and to processes for preparation thereof, to pharmaceuticalcomposition comprising the same, and to a method of using the sametherapeutically in the treatment of infectious diseases in human beingand animals.

Accordingly, it is one object of the present invention to provide3,7-disubstituted-3-cephem-4-carboxylic acid compounds andpharmaceutically acceptable salts thereof, which are active against anumber of pathogenic microorganisms.

Another object of the present invention is to provide processes for thepreparation of 3,7-disubstituted-3-cephem-4-carboxylic acid compoundsand pharmaceutically acceptable salts thereof.

A further object of the present invention is to provide pharmaceuticalcomposition comprising, as active ingredients, said3,7-disubstituted-3-cephem-4-carboxylic acid compounds andpharmaceutically acceptable salts thereof.

Still further object of the present invention is to provide a method forthe treatment of infectious diseases caused by pathogenic bacteria inhuman being and animals.

The object 3,7-disubstituted-3-cephem-4-carboxylic acid compounds arenovel and can be represented by the following general formula (I).##STR2## wherein R¹ is amino or a protected amino group,

R² is a group of the formula: --CONH--R⁵ (wherein R⁵ is aryl which mayhave suitable substituent(s) or a heterocyclic group which may havesuitable substituent(s)), a group of the formula: ##STR3## (wherein R⁶is hydrogen or lower alkyl) or a group of the formula: --NHCO--R⁵(wherein R⁵ is as defined above),

R³ is carboxy or a protected carboxy,

R⁴ is acyloxy or a heterocyclicthio group which may have suitablesubstituent(s) and

A is lower alkylene.

According to the present invention, the3,7-disubstituted-3-cephem-4-carboxylic acid compounds (I) can beprepared by various processes which are illustrated in the followingschemes. ##STR4## wherein R¹, R², R³, R⁴, R⁵ and A are each as definedabove,

R^(1a) is a protected amino,

R^(4a) is a heterocyclicthio group which may have suitablesubstituent(s),

R^(6a) is lower alkyl, and

Y is a group which can be substituted by a group of the formula:--R^(4a) in which R^(4a) is as defined above.

Among the starting compounds in the present invention, the compound(III) is novel and can be prepared by the process which are illustratedin the following schemes. ##STR5## wherein R¹, R², R⁵, R⁶ and A are eachas defined above,

X is hydroxy or its reactive derivative, and

R⁷ is amino having a protective group.

Regarding the object compounds (I), (Ia), (Ib), (Ic), (Id), (Ie), (If)and (Ig) and the starting compounds (III), (IIIa), (VIII), (X) and(XIX), it is to be understood that they include tautomeric isomers.

That is, in case that the group of the formula: ##STR6## (R¹ is asdefined above) is contained in the molecules of said object and startingcompounds, said group of the formula can also be alternativelyrepresented by its tautomeric formula: ##STR7## (R^(1') is imino or aprotected imino group). That is, the both of said groups are in thestate of equilibrium each other and such tautomerism can be representedby the following equilibrium. ##STR8## wherein R¹ and R^(1') are each asdefined above.

These types of tautomerism between the amino-compound and thecorresponding imino-compound as stated above have been well known in theliterature, and it is obvious to a person skilled in the arts that bothof the tautomeric isomers are easily convertible reciprocally and areincluded within the same category of the compound per se. Accordingly,the both of the tautomeric forms of the object compounds (I), (Ia),(Ib), (Ic), (Id), (Ie) (If) and (Ig) and the starting compounds (III),(IIIa) (VIII), (X) and (XIX) are clearly included within the scope ofthe present invention. In the present specification and claims, theobject and starting compounds including the group of such tautomericisomers are represented by using one of the expressions therefor, thatis the formula: ##STR9## only for the convenient sake.

Furthermore, regarding the object compounds (I), (Ia), (Ib), (Ic), (Id),(Ie), (If) and (Ig) and the starting compounds (III), (IIIa), (X) and(XIX) it is to be understood that said object and starting compoundsinclude syn isomer, anti isomer and a mixture thereof. For example, withregard to the object compound (I), syn isomer means one geometricalisomer having the partial structure represented by the followingformula: ##STR10## (wherein R¹, R² and A are each as defined above) andanti isomer means the other geometrical isomer having the partialstructure represented by the following formula: ##STR11## (wherein R¹,R² and A are each as defined above).

Regarding the other object and starting compounds as mentioned above,the syn isomer and the anti isomer can be also referred to the samegeometrical isomers as illustated for the compound (I).

Suitable pharmaceutically acceptable salts of the object compounds (I)are conventional non-toxic salt and include a metal salt such as analkali metal salt (e.g., sodium salt, potassium salt, etc.) and analkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), anammonium salt, an organic base salt (e.g., trimethylamine salt,triethylamine salt, pyridine salt, picoline salt, dicyclohexylaminesalt, N,N'-dibenzylethylenediamine salt, etc.), an organic acid salt(e.g., acetate, maleate, tartrate, methanesulfonate, benzenesulfonate,formate, toluenesulfonate, etc.), an inorganic acid salt (e.g.,hydrochloride, hydrobromide, sulfate, phosphate, etc.), or a salt withan amino acid (e.g., arginine, aspartic acid, glutamic acid, etc.), andthe like.

In the above and subsequent descriptions of the present specification,suitable examples and illustrations of the various definitions which thepresent invention include within the scope thereof are explained indetails as follows.

The term "lower" is intended to mean 1 to 6 carbon atoms, unlessotherwise indicated.

Suitable protected amino for R¹ may include an acylamino or an aminogroup substituted by a conventional protecting group such asar(lower)alkyl which may have at least one suitable substituent(s),(e.g., benzyl, trityl, etc.) or the like.

Suitable acyl moiety in the terms "acylamino" and "acyloxy" for R⁴ mayinclude carbamoyl, aliphatic acyl group and acyl group containing anaromatic or heterocyclic ring. And, suitable examples of the said acylmay be lower alkanoyl (e.g., formyl, acetyl, propionyl, butyryl,isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.);

lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, tertiarybutoxycarbonyl, pentyloxycarbonyl,hexyloxycarbonyl, etc.);

lower alkanesulfonyl (e.g., mesyl, ethanesulfonyl, propanesulfonyl,isopropanesulfonyl, butanesulfonyl, etc.);

arenesulfonyl (e.g., benzenesulfonyl, tosyl, etc.); aroyl (e.g.,benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, indancarbonyl, etc.);

ar(lower)alkanoyl (e.g., phenylacetyl, phenylpropionyl, etc.);

ar(lower)alkoxycarbonyl (e.g., benzyloxycarbonyl, phenethyloxycarbonyl,etc.), and the like.

The acyl moiety as stated above may have at least one suitablesubstituent(s) such as halogen (chlorine, bromine, fluorine and iodine)or the like.

Preferable examples of acylamino and acyloxy groups may include loweralkanoylamino and lower alkanoyloxy, respectively.

The aryl groups in the term "aryl which may have suitablesubstituent(s)" may include phenyl, tolyl, xylyl mesityl, cumenyl,naphthyl and the like. These groups may have one or more suitablesubstituent(s) such as halogen, hydroxy, carboxy, esterified carboxy asmentioned below or the like. In case that said aryl group have two ormore substituents, the substituents may be the same or different.

The heterocyclic moiety in the terms "heterocyclic group which may havesuitable substituent(s)" and "heterocyclicthio group which may havesuitable substituent(s)" means saturated or unsaturated, monocyclic orpolycyclic heterocyclic group containing at least one hetero-atom suchas an oxygen, sulfur, nitrogen atom and the like.

And, especially preferable heterocyclic group may be heterocyclic groupsuch as

unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl,pyrazolyl, pyridyl and its N-oxide, dihydropyridyl, pyrimidyl,pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl,1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g.1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.;

saturated 3 to 8-membered heteromonocyclic group containing 1 to 4nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl, piperidino,piperazinyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 4 nitrogenatom(s), for example, indolyl, isoindolyl, indolizynyl, benzimidazolyl,quinolyl, isoquinolyl, indazolyl, benzotriazolyl, etc.;

unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 2oxyen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl,isoxazolyl, oxadiazolyl, (e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl, etc.) etc.;

saturated 3 to 8-membered heteromonocyclic group containing 1 to 2oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholinyl,sydnonyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 2 oxygenatom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl,benzoxadiazolyl, etc.;

unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 2sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl,isothiazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.),dihydrothiazinyl, etc.;

saturated 3 to 8-membered heteromonocyclic group containing 1 to 2sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyl,etc.;

unsaturated 3 to 8 membered heteromonocyclic group containing 1 to 2sulfur atom(s), for example, thienyl, dihydrodithiinyl,dihydrodithiolyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 2 sulfuratom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolylbenzothiadiazolyl, etc.;

unsaturated 3 to 8-membered heteromonocyclic group containing an oxygenatom, for example, furyl, etc.; unsaturated 3 to 8-memberedheteromonocyclic group containing an oxygen atom and 1 to 2 sulfuratom(s), for example, dihydrooxathiinyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 2 sulfuratom(s), for example, benzothienyl, benzodithiinyl, etc.;

unsaturated condensed heterocyclic group containing an oxygen atom and 1to 2 sulfur atom(s), for example, benzoxathiinyl, etc. and the like.

The heterocyclic moieties as mentioned above may have at least onesubstituent(s) such as lower alkyl mentioned below,di(lower)alkylamino(lower)alkyl (e.g. dimethylaminomethyl,dimethylaminoethyl, diethylaminopropyl, diethylaminobutyl, etc.), loweralkenyl (e.g., vinyl, allyl, butenyl, etc.), aryl which may havesuitable substituent(s) as defined above, halogen mentioned below,amino(lower)alkyl (e.g., aminomethyl, aminoethyl, etc.),carboxy(lower)-alkyl (e.g., carboxymethyl, carboxyethyl, etc.), amino orthe like.

Preferable example of heterocyclic moieties having suitablesubstituent(s) may include tetrazolyl having lower alkyl (e.g.,methyltetrazolyl, ethyltetrazolyl, etc.), thiadiazolyl having loweralkyl (e.g., methylthiadiazolyl, ethylthiadiazolyl, etc.) and isoxazolylhaving lower alkyl and halogen substituted aryl (e.g.,5-methyl-3-chlorophenylisoxazolyl, 5-methyl-3-bromophenylisoxazolyl,5-ethyl-3-chlorophenylisoxazolyl, etc.),

Suitable lower alkyl means straight or branched one and may includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl,hexyl and the like.

Suitable protected carboxy may include an esterified carboxy and thelike, and suitable examples of the ester moiety in said esterifiedcarboxy may be the ones such as lower alkyl ester (e.g., methyl ester,ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester,pentyl ester, hexyl ester, 1-cyclopropylethyl ester, etc.) which mayhave at least one suitable substituent(s), for example, loweralkanoyloxy(lower)alkyl ester (e.g., acetoxymethyl ester,propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethylester, pivaloyloxymethyl ester, 2-acetoxyethyl ester,2-propionyloxyethyl ester, hexanoyloxymethyl ester, etc.), loweralkanesulfonyl(lower)alkyl ester (e.g., 2-mesylethyl ester, etc.) ormono (or di or tri)-halo(lower)alkyl ester (e.g., 2-iodoethyl ester,2,2,2-trichloroethyl ester, etc); lower alkenyl ester (e.g., vinylester, allyl ester, etc.); lower alkynyl ester (e.g., ethynyl ester,propynyl ester, etc.);

ar(lower)alkyl ester which may have at least one suitable substituent(s)(e.g., benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester,phenethyl ester, trityl ester, diphenylmethyl ester,bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester,4-hydroxy-3,5-ditertiarybutylbenzyl ester, etc.);

aryl ester which may have at least one suitable substituent(s) (e.g.,phenyl ester, 4-chlorophenyl ester, tolyl ester, tertiarybutylphenylester, xylyl ester, mesityl ester, cumenyl ester, etc.), and the like.

Preferable example of the esterified carboxy as mentioned above mayinclude lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,tert-butoxycarbonyl, pentyloxycarbonyl, tert-pentyloxycarbonyl,hexyloxycarbonyl, 1-cyclopropylethoxycarbonyl, etc.).

Suitable lower alkylene means straight or branched one and may includemethylene, ethylene, trimethylene, propylene, tetramethylene,pentamethylene, hexamethylene and the like.

Suitable hydroxy reactive derivative for X may include an acid residuesuch as halogen as mentioned above or the like.

Suitable amino having a protective group for R⁷ may include phthalimido,succinimido, ethoxycarbonylamino and the like, and preferablyphthalimido.

Suitable example of a group which can be substituted by a group of theformula: --R^(4a) may include an acid residue (e.g., azido, aforesaidhalogen, acyloxy, etc. and the like.

The preferable examples of the object compound (I) are exemplified asfollows.

Preferable example of R¹ is amino or lower alkanoylamino; R² is a groupof the formula: --CONH--R⁵ [wherein preferable example of R⁵ is arylgroup having at least one substituent(s), which may be the same ordifferent, such as halogen, hydroxy, carboxy or lower alkoxycarbonyl(more preferably, phenyl having at least one substituent(s) as mentionedabove); pyridyl or thiazolyl], a group of the formula: ##STR12##(wherein preferable example of R⁶ is hydrogen or lower alkyl) or a groupof the formula: --NHCO--R⁵ [wherein preferable example of R⁵ is aryl(more preferably, phenyl) having hydroxy and halogen as substituents orisoxazolyl having lower alkyl and halogen substituted aryl assubstituents (more preferably, isoxazolyl having lower alkyl and halogensubstituted phenyl)]; R³ is carboxy; R⁴ is lower alkanoyloxy,tetrazolylthio which may have lower alkyl group, thiadiazolylthio whichmay have lower alkyl group as substituent, or benzothiazolylthio; and Ais lower alkylene.

The processes for preparing the object compounds of the presentinvention are explained in details in the following.

Process 1

The object compound (I) or a salt thereof can be prepared by reactingthe compound (II) or its reactive derivative at the amino group or asalt thereof with the compound (III) or its reactive derivative at thecarboxy group or a salt thereof.

Suitable reactive derivative at the amino group of the compound (II) mayinclude Schiff's base type imino or its tautomeric enamine type isomerformed by the reaction of the compound (II) with a carbonyl compoundsuch as acetoacetic acid or the like; a silyl derivative formed by thereaction of the compound (II) with a silyl compound such asbis(trimethylsilyl)acetamide or the like; a derivative formed byreaction of the compound (II) with phosphorus trichloride or phosgene,and the like.

Suitable salt of the compounds (II) and (III) may include an acidaddition salt such as an organic acid salt (e.g., acetate, maleate,tartrate, benzenesulfonate, toluenesulfonate, etc.) or an inorganic acidsalt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.); ametal salt (e.g., sodium salt, potassium salt, calcium salt, magnesiumsalt, etc.); ammonium salt; an organic amine salt (e.g., triethylaminesalt, dicyclohexylamine salt, etc.), and the like.

Suitable reactive derivative at the carboxy group of the compound (III)may include an acid halide, an acid anhydride, an activated amide, anactivated ester, and the like. The suitable example may be an acidchloride, an acid azide; a mixed acid anhydride with an acid such assubstituted phosphoric acid (e.g., dialkylphosphoric acid,phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid,halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfurousacid, thiosulfuric acid, sulfuric acid, alkylcarbonic acid, aliphaticcarboxylic acid (e.g., pivalic acid, pentanoic acid, isopentanoic acid,2-ethylbutyric acid or trichloroacetic acid, etc.) or aromaticcarboxylic acid (e.g. benzoic acid, etc.); a symmetrical acid anhydride;an activated amide with imidazole, 4-substituted imidazole,dimethylpyrazole, triazole or tetrazole; or an activated ester (e.g.,cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl[(CH₃)₂ N⁺=CH--]ester, vinyl ester, propargyl ester, p-nitrophenyl ester,2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester,mesyl phenyl ester, phenylazophenyl ester, phenyl thioester,p-nitrophenyl thioester p-cresyl thioester, carboxymethyl thioester,pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester,etc.), or an ester with a N-hydroxy compound (e.g.,N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone,N-hydroxysuccinimide, N-hydroxyphthalimide,1-hydroxy-6-chloro-1H-benzotriazole, etc.), and the like. These reactivederivatives can optionally be selected from them according to the kindof the compound (III) to be used.

The reaction is usually carried out in a conventional solvent such aswater, acetone, dioxane, acetonitrile, chloroform, methylene chloride,ethylene chloride, tetrahydrofuran, ethyl acetate,N,N-dimethylformamide, pyridine or any other organic solvents which donot adversely influence the reaction. These conventional solvents mayalso be used in a mixture with water.

When the compound (III) is used in free acid form or its salt form inthe reaction, the reaction is preferably carried out in the presence ofa conventional condensing agent such as N,N'-dicyclohexylcarbodiimide;N-cyclohexyl-N'-morpholinoethylcarbodiimide;N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide;N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide;N-ethyl-N'-(3-diethylaminopropyl)carbodiimide; N,N-carbonylbis-(2-methylimidazole); pentamethyleneketene-N-cyclohexylimine;diphenylketene-N-cyclohexylimine; ethoxyacetylene;1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate;isopropyl polyphosphate; phosphorus oxychloride; phosphorus trichloride;thionyl chloride; oxalyl chloride; triphenylphosphine;2-ethyl-7-hydroxybenzisoxazolium salt;2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intra-molecular salt;1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; so-calledVilsmeier reagent prepared by the reaction of dimethylformamide withthionyl chloride, phosgene, phosphorus oxychloride, etc.; or the like.

The reaction may also be carried out in the presence of an inorganic ororganic base such as an alkali metal bicarbonate, tri(lower)alkylamine,pyridine, N-(lower)alkylmorphorine, N,N-di(lower)alkylbenzylamine, orthe like. The reaction temperature is not critical, and the reaction isusually carried out under cooling or at ambient temperature.

In the present reaction, a syn isomer of the object compound (I) can beobtained preferably by conducting the present reaction of the compound(II) with the corresponding syn isomer of the starting compound (III),for example, in the presence of a Vilsmeier reagent as mentioned aboveetc. and under around neutral condition.

Process 2

The object compound (Ib) or a salt thereof can be prepared by subjectingthe compound (Ia) or a salt thereof to elimination reaction of the aminoprotective group.

Suitable salt of the compound (Ia) can be referred to the metal salt,ammonium salt and organic amine salt exemplified for the compound (II).

The elimination reaction is carried out in accordance with aconventional method such as hydrolysis; reduction; a method treating thecompound (Ia) wherein R^(1a) is acylamino with iminohalogenating agent,iminoetherifying agent and then, if necessary, hydrolyzing theresultant; or the like. The hydrolysis may include a method using anacid or base or hydrazine and the like. These methods may be selecteddepending on the kind of the protective groups to be eliminated.

Among these methods, hydrolysis using an acid is one of the most commonand preferable method for eliminating the protective groups such assubstituted or unsubstituted alkoxycarbonyl, for example,tert-pentyloxycarbonyl, lower alkanoyl (e.g., formyl, acetyl, etc.),cycloalkoxycarbonyl, substituted or unsubstituted aralkoxycarbonyl,aralkyl (e.g., trityl), substituted phenylthio, substitutedaralkylidene, substituted alkylidene, substituted cycloalkylidene or thelike. Suitable acid includes an organic or inorganic acid such as formicacid, trifluoroacetic acid, benenesulfonic acid, p-toluenesulfonic acid,hydrochloric acid and the like, and the most suitable acid is an acidwhich can easily be removed from the reaction mixture by a conventionalmanner such as distillation under reduced pressure, for example, formicacid, trifluoroacetic acid, hydrochloric acid, etc. The acids can beselected according to the kind of the protective group to be eliminated.When the elimination reaction is conducted with an acid it can becarried out in the presence or absence of a solvent. Suitable solventincludes water, a conventional organic solvent or a mixture thereof.

The elimination reaction using trifluoroacetic acid may be carried outin the presence of anisole. The hydrolysis using hydrazine is commonlyapplied for eliminating a phthaloyl, succinyl type aminoprotectivegroup.

The elimination using base is used for eliminating an acyl group such astrifluoroacetyl. Suitable base may include an inorganic base and anorganic base.

The reductive elimination is generally applied for eliminating theprotective group, for example, haloalkoxycarbonyl (e.g.,trichloroethoxycarbonyl, etc.), substituted or unsubstituted aralkoxycarbonyl (e.g., benzyloxycarbonyl, etc.), 2-pyridylmethoxycarbonyl, etc.Suitable reduction may include, for example, reduction with an alkalimetal borohydride (e.g., sodium borohydride, etc.), reduction with acombination of a metal (e.g., tin, zinc, iron, etc.) or the said metaltogether with a metal salt compound (e.g., chromous chloride, chromousacetate, etc.) and an organic or inorganic acid (e.g., acetic acid,propionic acid, hydrochloric acid, etc.); and catalytic reduction.Suitable catalyst includes a conventional one, for example, Randynickel, platinum oxide, palladium on charcoal and the like.

Among the protective groups, the acyl group can generally be eliminatedby hydrolysis. Especially, halogen substituted-alkoxycarbonyl and8-quinolyloxycarbonyl groups are usually eliminated by treating with aheavy metal such as copper, zinc, or the like.

Among the protective groups, the acyl group can also be eliminated bytreating with an iminohalogenating agent (e.g., phosphorus oxychloride,etc.) and an iminoetherifying agent such as lower alkanol (e.g.,methanol, ethanol, etc.), if necessary, followed by hydrolysis.

The reaction temperature is not critical and may suitably be selected inaccordance with the kind of the protective group for the amino group andthe elimination method as mentioned above, and the reaction ispreferably carried out under a mild condition such as under cooling orat slightly elevated temperature.

The present invention includes, within its scope, the cases that anesterified carboxy being a substituent on aryl for R⁵ is transformedinto the free carboxy group and a protected carboxy for R³ istransformed into the free carboxy group according to the reactionconditions and/or kinds of the carboxy protective group during thereaction or the post-treating step of the present process.

Process 3

The object compound (Id) or a salt thereof can be prepared by subjectinga compound (Ic) or a salt thereof to the elimination reaction ofphosphoric acid ester.

Suitable salts of the compound (Ic) can be referred to the onesexemplified for the compound (Ia).

This elimination reaction can be conducted, for example, by reacting acompound (Ic) or a salt thereof with a trialkylsilyl halide (e.g.trimethylsilyl bromide, trimethylsilyl iodide, trimethylsilylchloride,etc.), preferably in the presence of a silylating agent such asbis(trimethylsilyl)acetamide, trimethylsilylacetamide and the like.

The reaction is preferably carried out in a solvent such as methylenechloride or any other organic ones which do not adversely influence thereaction. The reaction temperature is not critical and the reaction isusually carried out under relatively mild conditions such as aroundambient temperature.

The present invention includes, within its scope, the case that aprotected amino for R¹ is converted into the free amino group accordingto reaction conditions and/or kinds of the amino protective group duringthe reaction or the post-treating step of the present process.

Process 4

The object compound (If) or a salt thereof can be prepared by reacting acompound (Ie) or a salt thereof with a compound (XVIII) or its reactivederivative at the mercapto group.

Suitable salts of the compound (Ie) are referred to the ones exemplifiedfor the compound (I).

Suitable reactive derivative at the mercapto group in the compound(XVIII) may include a metal salt such as an alkali metal salt (e.g.sodium salt potassium salt, etc.), an alkaline earth metal salt (e.g.,magnesium salt, etc.) or the like.

The reaction is usually carried out in a solvent such as water, acetone,chloroform, nitrobenzene, methylene chloride, ethylene chloride,dimethylformamide, methanol, ethanol, ether, tetrahydrofuran or anyother conventional solvents which do not adversely influence thereaction, preferably in ones having strong polarity, which may be usedas a mixture with water.

When the compound (Ie) and/or the compound (XVIII) are used in free formin the reactions, the reaction is preferably carried out in the presenceof a base, for example, an organic or an inorganic base such as alkalimetal hydroxide, alkali metal carbonate, alkali metal bicarbonate,trialkylamine, pyridine or the like, and preferably carried out aroundneutral conditions. The reaction temperature is not critical and thereaction is usually carried out at ambient temperature or under warming.

The present invention includes, within its scope, the cases that aprotected amino and/or a protected carboxy group are converted into thecorresponding free amino and/or the free carboxy group during thereaction or the post-treating step of the present process.

Process 5

The object compound (Ig) or a salt thereof can be prepared by reactingthe compound (XIX) or its reactive derivative at the amino group or asalt thereof with the compound (XI) or its reactive derivative at thecarboxy group or a salt thereof.

Suitable reactive derivative at the amino group and salts of thecompound (XIX) can be referred to the ones exemplified for the compound(II).

Suitable reactive derivative at the carboxy group and salts of thecompound (XI) can be referred to the ones exemplified for the compound(III).

The present reaction is carried out substantially in the same manner asillustrated in Process 1.

Processes for the preparation of the starting compounds (III) areexplained in detail as follows.

Preparation 1. (IV)+(V)→(VI): [Process (A)]

The compound (VI) can be prepared by reacting a compound (IV) with acompound (V).

The reaction is preferably carried out in the presence of a base asexemplified in Process 1 in case that X is an acid residue and in thepresence of a condensing agent, for example, one formed bytriphenylphosphine and diethyl azoformate in case that X is hydroxy,respectively.

The reaction is usually carried out in a solvent such as acetonitrile,dimethylformamide, tetrahydrofuran or any other solvents which do notadversely influence the reaction. The reaction temperature is notcritical and the reaction is usually carried out from cooling to heatingaround a boiling point of the solvent used.

Preparation 2. (VI)→(VII): [Process (A)]

The compound (VII) or a salt thereof can be prepared by subjecting acompound (VI) to elimination reaction of the amino protective group.

This elimination reaction of the amino protective group of the compound(VI) can be carried out in a similar manner to that of aforementionedProcess 2.

Suitable solvents include water, ethanol, chloroform, diethyl ether andthe like. The reaction temperature is not critical and the reaction isusually carried out under warming or heating.

Preparation 3. (VII)+(VIII)→(III): [Process (A)]

The compound (III) or a salt thereof can be prepared by reacting acompound (VII) or a salt thereof with a compound (VIII).

Suitable salts of the compound (VII) include an inorganic acid salt(e.g., hydrochloride, hydrobromide, sulfate, etc.), an organic acid salt(e.g., acetate, p-toluenesulfonate, etc.) and the like.

The reaction is usually carried out in a conventional solvent such aswater, alcohol (e.g., methanol, ethanol, etc.), a mixture thereof or anyother ones which do not adversely influence the reaction.

When the compound (VII) is used in its salt form, the reaction ispreferably carried out in the presence of an organic or an inorganicbase as exemplified before.

The reaction temperature is not critical, and the reaction is usuallycarried out from cooling to heating.

In the present reaction, a syn isomer of the compound (III) can beobtained preferably by conducting the present reaction under aroundneutral conditions.

Preparation 4. (IX)+(VIII)→(X): [Process (B)]

The compound (X) or a salt thereof can be prepared by reacting acompound (IX) or a salt thereof with a compound (VIII).

Suitable salts of the compound (IX) can be referred to the ones asexemplified for the compound (VII).

This reaction is carried out in a similar manner to that of Preparation3 [(VII)+(VIII)→(III)].

Preparation 5. (X)+(XI)→(IIIa)[Process (B)]

The compound (IIIa) or a salt thereof can be prepared by reacting acompound (X) or a salt thereof with a compound (XI) or its reactivederivative at the carboxy group or a salt thereof.

Suitable salts of the compound (X) can be referred to the onesexemplified for the compound (III) and suitable reactive derivative atthe carboxy group and salts of the compound (XI) can be referred to theones exemplified for the compound (III), respectively.

The present reaction is carried out in a similar manner to that ofaforesaid Process 1.

Preparation 6. (XII)+(XIII)→(XIV): [Process (C)]

The compound (XIV) can be prepared by reacting a compound (XII) with acompound (XIII).

The present reaction can be carried out even in the absence of asolvent. The reaction temperature is not critical and the reaction isusually carried out under heating.

Preparation 7. (XV)+(XVI)→(XVII): [Process (D)]

The compound (XVII) can be prepared by reacting a compound (XV) or asalt thereof with a compound (XVI) or its reactive derivative at thecarboxy group or a salt thereof.

Suitable salts of the compound (XV) can be referred to the onesexemplified for the compound (VII) and suitable reactive derivative atthe carboxy group and salt of the compound (XVI) can be referred to theones exemplified for the compound (III), respectively.

This reaction is carried out in a similar manner to that ofaforementioned Process 1.

The present invention includes, within its scope, the cases that the onetype of tautomeric isomers is converted into the other type of isomerduring the reaction and/or the post-treating step of the each process.

In case that the object compound (I) is obtained in a form of the freeacid at the 4-position and/or in case that the compound (I) has freeamino group, it may be transformed into its pharmaceutically acceptablesalt as aforementioned by a conventional method.

The object compounds (I) and pharmaceutically acceptable salt thereof ofthe present invention are novel compounds which exhibit highantibacterial activity and inhibit the growth of a wide variety ofpathogenic microorganisms including Gram-positive and Gram-negativebacteria. For therapeutic purpose, the compounds according to thepresent invention can be used in the form of pharmaceutical preparationwhich contain said compounds, as an active ingredient, in admixture witha pharmaceutically acceptable carriers such as an organic or inorganicsolid or liquid excipient suitable for oral, parenteral or externaladministration. The pharmaceutical preparations may be capsules,tablets, dragees, ointments or suppositories, solutions, suspensions,emulsions, and the like. If desired, there may be included in the abovepreparations auxiliary substances, stabilizing agents wetting oremulsifying agents, buffers and other commonly used additives.

While the dosages of the compounds will vary depend upon the age andcondition of the patient, an average single dose of about 10 mg., 50mg., 100 mg., 250 mg., 500 mg., and 1000 mg. of the compounds accordingto the present invention was proved to be effective for treatinginfectious diseases caused by pathogenic bacteria. In general, amountsbetween 1 mg/body and about 6,000 mg/body or even more may beadministered per day.

In order to illustrate the usefulness of the object compounds,anti-microbial activities of some representative compounds of thepresent invention against some test strains of pathogenic bacteria areshown in their minimal inhibitory concentrations below.

Test Method

In vitro antibacterial activity was determined by the two-foldagar-plate dilution method as described below.

One loopful of an overnight culture of each test strain inTrypticase-soy broth (10⁸ viable cells per ml) was streaked on heartinfusion agar (HI-agar) containing graded concentrations ofrepresentative test compound, and the minimal inhibitory concentration(MIC) was expressed in terms of μg/ml. after incubation at 37° C. for 20hours.

Test compounds

(1)7-[2-{N-(2-Hydroxy-5-chlorophenyl)carbamoylmethoxyimino}-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer)

(2)7-[2-(2-Phosphonoethoxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer)

(3)7-[2-Phosphonomethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

(4)7-[2-{N-(3-Pyridyl)carbamoylmethoxyimino}-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

Test result

    ______________________________________                                                    M.I.C. (μg/ml)                                                               Com-    Com-     Com-   Com-                                                  pound   pound    pound  pound                                   Test Microorganism                                                                          (1)     (2)      (3)    (4)                                     ______________________________________                                        Proteus vulgaris                                                                            6.25    0.025    0.10   0.39                                    IAM-1025                                                                      Pseudomonas aeruginosa                                                                      6.25    25       3.13   3.13                                    NCTC-10490                                                                    Pseudimonas aeruginosa                                                                      12.5    25       6.25   6.25                                    721                                                                           Proteus mirabilis 501                                                                       0.78    0.0125   0.025  0.39                                    ______________________________________                                    

The following Preparations and Examples are given for the purpose ofillustrating the present invention.

PREPARATION OF THE STARTING COMPOUND Preparation 1 (1) Preparation ofN-(2-Hydroxy-5-chlorophenyl)-2-bromoacetamide

To a mixture of 2-amino-4-chlorophenol (19.50 g.) andN,N-dimethylaniline (19.90 g.) in dry acetone (200 ml.) was addeddropwise bromoacetyl bromide (33.2 g.) over a period of 15 minutes underice-cooling at below 10° C. with stirring and stirring was continued for45 minutes at the same temperature. The reaction mixture was evaporatedand to the residue were added ethyl acetate and water. The ethyl acetatelayer was washed with 5% hydrochloric acid (twice), water, 5% aqueoussolution of sodium bicarbonate, water (twice) and a saturated aqueoussolution of sodium chloride successively, dried over magnesium sulfate,treated with activated charcoal and then evaporated. The residue wasrecrystallized from a mixture of ethyl acetate and diisopropyl ether togive the title compound (18.91 g.).

I.R. (Nujol): 3390, 3150, 1650 cm⁻¹.

N.M.R. (DMSO-d₆, δ): 4.22 (2H, s), 6.8-7.2 (2H, m), 8.05 (1H, d, J=2Hz).

(2) Preparation ofN-(2-Hydroxy-5-chlorophenyl)-2-(phthalimidoxy)acetamide

To a mixture of N-hydroxyphthalimide (10.84 g.) and triethylamine (6.72g.) in dry acetonitrile (160 ml.) was addedN-(2-hydroxy-5-chlorophenyl)-2-bromoacetamide (17.6 g.) with stirringunder ice-cooling and stirring was continued for 1.5 hours at roomtemperature. The precipitates were separated from the reaction mixtureby filtration, washed successively with acetonitrile, ethyl acetate andwater to give the title compound (18.4 g.).

I.R. (Nujol): 3400, 3100, 1800, 1740, 1660 cm⁻¹.

N.M.R. (DMSO-d₆ +D₂ O, δ): 4.92 (2H, s), 6.9-7.1 (2H, m), 7.90 (4H, s),8.08 (1H, d, J=2 Hz).

(3) N-(2-Hydroxy-5-chlorophenyl)-2-(aminooxy)-acetamide

A mixture of N-(2-hydroxy-5-chlorophenyl)-2-(phthalimidoxy)acetamide(10.0 g.) and hydrazine.hydrate (1.442 g.) in ethanol (100 ml.) wasrefluxed under heating for 2 hours. After allowing the reaction mixtureto stand under ice-cooling, the precipitates were separated byfiltration and washed with ethanol. The combined filtrate and washingwas evaporated and to the residue was added ethyl acetate. After removalof insoluble substances by filtration, the filtrate was extracted with5% hydrochloric acid. The extract was washed with ethyl acetate,adjusted to about pH 7 with an aqueous solution of sodium bicarbonateand then reextracted with ethyl acetate. The ethyl acetate extract waswashed with an aqueous solution of sodium chloride, dried over magnesiumsulfate and then evaporated to give crystals of the title compound (4.59g.).

I.R. (Nujol): 3330, 3260, 1690 cm⁻¹.

N.M.R. (DMSO-d₆ +D₂ O, δ): 4.20 (2H, s), 6.9-7.1 (2H, m), 8.1-8.2 (1H,m).

(4)2-[N-(2-Hydroxy-5-chlorophenyl)carbamoylmethoxyimino]-2-(2-formamidothiazol-4-yl)aceticacid (syn isomer)

A mixture of 2-(2-formamidothiazol-4-yl)glyoxylic acid (2.79 g.) andN-(2-hydroxy-5-chlorophenyl)-2-(aminooxy)-acetamide (3.32 g.) in ethanol(30 ml.) was stirred for 5 hours at room temperature. The reactionmixture was evaporated to dryness and to the residue was added a mixtureof ethyl acetate, water and 10% hydrochloric acid followed by stirring.The ethyl acetate layer was separated, washed with diluted hydrochloricacid and an aqueous solution of sodium chloride, dried over magnesiumsulfate, concentrated to a small volume and allowed to stand underice-cooling. The resulting precipitates were collected by filtration,washed with ethyl acetate and then dried under reduced pressure to givethe title compound (4.59 g.).

I.R. (Nujol): 3300, 1735, 1695, 1649 cm⁻¹.

N.M.R. (DMSO-d₆ +D₂ O, δ): 4.83 (2H, s), 6.8-7.2 (2H, m), 7.63 (1H, s),8.15 (1H, d, J=2 Hz), 8.55 (1H, s).

Preparation 2 (1) Preparation of Diethyl(phthalimidoxymethyl)-phosphonate

To a mixture of diethyl hydroxymethylphosphonate (18.4 g.),N-hydroxyphthalimide (12.6 g.) and triphenylphosphine (28.8 g.) intetrahydrofuran (270 ml.) was added dropwise diethyl azoformate (21.0g.) under ice-water cooling followed by stirring at room temperatureovernight. The reaction mixture was evaporated and to the residue wasadded diethyl ether (300 ml.) followed by stirring for 30 minutes underice-cooling. The resulting mixture was filtered to remove insolublesubstances and the filtrate was concentrated.

The residue was chromatographed on silica gel (600 g.) using a mixtureof benzene and ethyl acetate (1:1) as an eluent. Fractions containing amixture of the desired compound and triphenylphosphineoxide wereevaporated to dryness and to the residue was added diethyl ether. Theresulting mixture was filtered to remove insoluble materials and thenevaporated to give the crude title compound (19.0 g.).

N.M.R. (CDCl₃, δ): 2.36 (6H, t, J=7 Hz), 4.25 (4H, d, t, J=14, 7 Hz),4.56 (2H, d, J=10 Hz), 7.2-7.9 (13H, m).

Thus obtained product was used in the next step reaction without furtherpurification.

(2) Preparation of Diethyl (aminooxymethyl)-phosphonate

A mixture of diethyl (phthalimidoxymethyl)phosphonate (14.48 g.) andhydrazine hydrate (2.32 g.) in ethanol (130 ml.) was refluxed underheating for 2 hours. After cooling, the reaction mixture was filtered toseparate insoluble substances, which were washed with ethanol. Thecombined filtrate and washing was concentrated after addition ofchloroform to the concentrate, the resulting mixture was filtered toremove insoluble substances, which were washed with chloroform. Thecombined filtrate and washing was again concentrated and then theconcentrate was dissolved in ethyl acetate. To the ethyl acetatesolution were added water and 10% hydrochloric acid followed by shaking(so that the pH became about 2) and separation of ethyl acetate layer.After repeating these operations twice, the remaining aqueous layerswere combined, washed with ethyl acetate, adjusted to pH about 4 with anaqueous solution of sodium bicarbonate and then concentrated underreduced pressure (the weight of the concentrate: about 25 g.). There wasobtained the concentrate containing the title compound. Thus obtainedconcentrate was used directly in the next step reaction.

(3) Preparation of2-(O,O-Diethylphosphono)-methoxyimino-2-(2-formamidothiazol-4-yl)aceticacid (syn isomer)

To the concentrate containing diethyl (aminooxymethyl)-phosphonateobtained in Preparation 2-(2) were added ethanol (80 ml.) and2-(2-formamidothiazol-4-yl)glyoxylic acid (5.80 g.) followed by stirringfor an hour at room temperature. The reaction mixture was adjusted to pHabout 7 with a saturated aqueous solution of sodium bicarbonate andevaporated. After addition of a small amount of water to the residue,the resulting mixture was washed with ethyl acetate, and then adjustedto pH 2 with 10% hydrochloric acid whereby an oily substance had formed,which was extracted with ethyl acetate. The extract was washed with asmall amount of water, dried over magnesium sulfate, treated withactivated characoal and then evaporated to give the foamy title compound(9.35 g.).

I.R. (K Br): 1740, 1700 cm⁻¹.

N.M.R. (CDCl₃, δ): 1.33 (6H, t, J=7 Hz), 4.27 (4H, d, t, J=15, 7 Hz),4.70 (2H, d, J=7 Hz), 7.43 (1H, s), 8.70 (1H, s).

Preparation 3 (1) Preparation of Diethyl(2-Phthalimidoxyethyl)phosphonate

A mixture of N-(2-bromoethoxy)phthalimide (2.0 g.) and triethylphosphite(2.46 g.) was stirred for 4 hours at 155° to 160° C. After removal ofexcess triethylphosphite from the reaction mixture, an oily residue wasdissolved in ethyl acetate. This solution was washed successively withwater, an aqueous solution of sodium bicarbonate and water, dried andthen evaporated to give an oil (3.3 g.), which was chromatographed onsilica gel (90 g.) using ethyl acetate as an eluent to give the titlecompound (0.9 g.).

I.R. (Nujol): 1782, 1730 cm⁻¹.

N.M.R. (CDCl₃, δ): 1.33 (6H, t, J=7 Hz), 2.33 (2H, d, t, J=20, 8 Hz),3.8-4.7 (6H, m), 7.8 (4H, s).

(2) Preparation of Diethyl (2-aminooxyethyl)phosphonate

A mixture of diethyl (2-phthalimidoxyethyl)phosphonate (20 g.) andhydrazine.hydrate (3.06 g.) in ethanol (200 ml.) was refluxed underheating for 2 hours with stirring. After cooling, the reaction mixturewas filtered to separate insoluble materials, which were washed withchloroform. The combined filtrate and washing was evaporated and to theresidue was added chloroform. The mixture was filtered to removeinsoluble substances and the filtrate was evaporated. The residue wasdissolved in chloroform, treated with activated charcoal and evaporatedto give the oily title compound (12.1 g.).

I.R. (Film): 3500, 3350, 3280, 3200 cm⁻¹.

N.M.R. (CDCl₃, δ): 1.28 (6H, t, J=7 Hz), 2.10 (2H, d, t, J=19, 7 Hz),3.6-4.4 (6H, m), 5.45 (2H, broad s).

(3) Preparation of2-[2-(O,O-Diethylphosphono)ethoxyimino]-2-(2-formamidothiazol-4-yl)aceticacid (syn isomer)

A mixture of 2-(2-formamidothiazol-4-yl)glyoxylic acid (6 g.) anddiethyl (2-aminooxyethyl)phosphonate (7.09 g.) in ethanol (60 ml.) wasstirred for 4 hours at room temperature. The reaction mixture wasevaporated to dryness and the residue was dissolved in ethyl acetate.This solution was washed successively with 5% hydrochloric acid andwater, dried and then evaporated to give the viscous title compound(11.1 g.).

I.R. (CHCl₃):

1745, 1710 cm⁻¹

N.M.R. (CDCl₃, δ): 1.30 (6H, t, J=7 Hz), 2.0-2.7 (2H, m), 3.8-5.0 (6H,m), 7.40 (1H, s), 8.73 (1H, s).

Preparation 4 (1) Preparation of N-(3-Pyridyl)-2-bromoacetamide

To a mixture of 3-aminopyridine (11 g.) and triethylamine (13.0 g.) indry ethyl acetate (300 ml.) was added a solution of bromoacetyl bromide(26.0 g.) in dry ethyl acetate (26 ml.) over a period of 30 minutes withstirring at 0° to 5° C. and stirring was continued for an additional 2hours at the same temperature. To the reaction mixture was added achilled aqueous solution of sodium bicarbonate. After shaking well, theethyl acetate layer was separated, washed successively with water, anaqueous solution of sodium bicarbonate and water, dried and thenconcentrated. There was obtained concentrate (200 ml.) containing thetitle compound. Thus obtained concentrate was used directly in the nextstep reaction without further purification.

(2) Preparation of N-(3-Pyridyl)-2-(phthalimidoxy)-acetamide

To a mixture of N-hydroxyphthalimide (17.2 g.) and triethylamide (10.6g.) in acetonitrile (200 ml.) was added the concentrate containingN-(3-pyridyl)-2-bromoacetamide obtained in preparation 4-(1) withstirring at room temperature and stirring was continued for an hour at45 go 50° C. To the reaction mixture was added ethyl acetate and water.After shaking well, the ethyl acetate layer was separated, washedsuccessively with water, an aqueous solution of sodium bicarbonate andwater, dried, treated and activated charcoal and then concentrated to avolume of 100 to 150 ml. The concentrate was filtered to give the titlecompound (10.7 g.). The filtrate was evaporated and the residue waswashed with diethyl ether to give the same compound (1.9 g.). Totalyield: 12.6 g.

I.R. (Nujol): 1795, 1740, 1695 cm⁻¹.

N.M.R. (DMSO-d₆, δ): 4.86 (2H, s), 7.38 (1H, d,d, J=8, 4 Hz), 7.88 (4H,s), 8.08 (1H, d,d, J=8, 2 Hz), 8.32 (1H, d, J=4 Hz), 8.78 (1H, d, J=2Hz)

(3) Preparation of N-(3-Pyridyl)-2-(aminooxy)-acetamide

A mixture of N-(3-pyridyl)-2-(phthalimidoxy)acetamide (7.8 g.) andhydrazine hydrate (1.3 g.) in ethanol (80 ml.) was refluxed underheating for 1.5 hours with stirring. The reaction mixture was cooled andthen insoluble substances were filtered out. The filtrate was evaporatedand to the residue were added 5% hydrochloric acid and water. Theresulting mixture was filtered to remove insoluble substances and thenthe filtrate (pH 1 to 2) was concentrated to a volume of 30 ml. to givethe concentrate containing the title compound. Thus obtained concentratewas used directly in the next step reaction.

(4) Preparation of2-[N-(3-Pyridyl)carbamoylmethoxyimino]-2-(2-formamidothiazol-4-yl)aceticacid (syn isomer)

The concentrate (30 ml.) containing N-(3-pyridyl)-2-(aminooxy)-acetamidewhich was obtained in Preparation 4-(3) was adjusted to pH 3 to 4 withsodium bicarbonate followed by addition of ethanol (100 ml.) and2-(2-formamidothiazol-4-yl)-glyoxylic acid (4.0 g.) at 15° to 20° C. Theresulting mixture was again adjusted to pH 3 to 4 with sodiumbicarbonate and then stirred for 3 hours at 18° to 20° C. The reactionmixture was evaporated and the precipitates were collected by filtrationand washed with a mixture of water and ethanol to give crystals (6.6g.). The crystals were dissolved in a mixture of ethanol (20 ml.), water(80 ml.) and sodium bicarbonate (2.38 g.) and then insoluble substanceswere filtered out. To the filtrate was added 1N hydrochloric acid (28.5ml.) so that the pH was adjusted to pH 3 to 4. The precipitates werecollected by filtration and dried to give crystals of the title compound(6.3 g.).

I.R. (Nujol): 3180, 3050, 1700, 1600 cm⁻¹.

N.M.R. (D₂ O+NaHCO₃, δ): 5.00 (2H, s), 7.45 (1H, d,d, J=8, 4 Hz), 7.62(1H, s), 7.9-8.2 (1H, m), 8.37 (1H, d,d, J=4, 2 Hz), 8.63 (1H, s), 8.77(1H, d, J=2 Hz).

Preparation 5 (1) Preparation of tert-Butyl 2-nitrobenzoate

A mixture of 2-nitrobenzoic acid (25.0 g.) and thionyl chloride (50 ml.)was refluxed for an hour and then evaporated. To the residue was addedbenzene (125 ml.) followed by removal of benzene. To the residue wereadded benzene (125 ml.), pyridine (23.7 g.) tert-butyl alcohol (22.2 g.)under ice-cooling and then the resulting solution was refluxed underheating for 2 hours. The reaction mixture was poured into ice water. Thebenzene layer was separated, washed successively with water, 1N aqueoussolution of sodium hydroxide (twice), water 1M aqueous solution ofcitric acid (twice), water and an aqueous solution of sodium chloride,dried over magnesium sulfate and then treated with activated charcoal.Thus obtained organic layer was chromatographed on silica gel (150 g.)eluting with a mixture of benzene and n-hexane (1:1) to give a yellowishoil of the title compound (23.6 g.)

I.R. (Film): 1737, 1540, 1373, 1310, 1232 cm⁻¹.

N.M.R. (CDCl₃, δ): 1.55 (9H, s), 7.17-8.0 (5H, m).

(2) Preparation of tert-Butyl 2-aminobenzoate

A mixture of tert-butyl 2-nitrobenzoate (2.1 g.) in methanol (200 ml.)was hydrogenated over palladium-carbon (2 g.) with shaking atatmospheric pressure and room temperature for 3.5 hours. The reactionmixture was filtered to remove the catalyst and then evaporated.

To the residue were successively added diethyl ether and an aqueoussolution of sodium chloride followed by shaking. The organic layer wasseparated, dried over magnesium sulfate, treated with activated charcoaland then evaporated to give an oil of the title compound (16.13 g.).

I.R. (Film): 3520, 3420, 1690, 1610, 1592, 1303, 1252, 1160 cm⁻¹.

N.M.R. (CCl₄, δ): 1.53 (9H, s), 5.67 (2H, broad s), 7.83-6.30 (4H, m).

(3) Preparation of N-(2-tert-Butoxycarbonylphenyl)-2-bromoacetamide

To a mixture of tert-butyl 2-aminobenzoate (5.79 g.), triethylamine(3.99 g.) in methylene chloride (100 ml.) was added dropwise bromoacetylbromide (8.01 g.) over a period of 15 minutes with stirring underice-cooling at 5° to 10° C. followed by stirring for 1.75 hours at thesame temperature. The reaction mixture was washed successively with 1Maqueous solution of citric acid (50 ml.×2), water a satirated aqueoussolution of sodium bicarbonate (25 ml.×2), water and an aqueous solutionof sodium chloride, dried over magnesium, treated with activatedcharcoal and then evaporated to give an oil of the title compound (9.65g.).

I.R. (Film): 3280, 1690, 1582, 1530, 1450, 1144 cm⁻¹.

N.M.R. (CCl₄, δ): 1.60 (9H, s), 3.88 (2H, s), 8.75-6.83 (4H, m), 11.75(1H, broad s).

(4) The following compound was prepared by a procedure similar to thatdescribed in Preparation 1-(2) or Preparation 4-(2).

tert-Butyl 2-(2-phthalimidoxy)acetamidobenzoate (crystal), mp. 142° to144° C.

I.R. (Nujol): 3200, 1792, 1745, 1703, 1685, 1525, 1142 700 cm⁻¹.

N.M.R. (DMSO-d₆, δ): 1.58 (9H, s), 4.93 (2H, s), 8.5-7.1 (8H, m), 11.40(1H, broad s).

(5) The following compound was prepared by a procedure similar to thatdescribed in Preparation 1-(3), 2-(2), 3-(2) or 4-(3).

tert-Butyl 2-(2-aminooxyacetamido)benzoate, pm. 87° to 89° C.

I.R. (Nujol): 3300, 1700, 1683, 1592, 1522, 1283, 1162, 1143 cm⁻¹.

N.M.R. (CDCl₃, δ): 7.87-7.0 (4H, m), 6.06 (2H, broad s), 4.28 (2H, s),1.62 (9H, s).

(6) The following compound was prepared by a procedure similar to thatdescribed in Preparation 1-(4), 2-(3), 3-(3) or 4-(4).

2-[N-(2-tert-Butoxycarbonylphenyl)carbamoylmethoxyimino]-2-[2-formamidothiazol-4-yl)aceticacid (syn isomer), mp. 159°-161° C. (dec.).

I.R. (Nujol): 3200, 1745, 1700, 1675, 1598, 1550, 1270 cm⁻¹.

N.M.R. (DMSO-d₆, δ): 1.43 (9H, s), 4.82 (2H, s), 8.70-7.03 (5H, m),11.43 (1H, s), 12.68 (1H, broad s).

Preparation 6

(1) The following compound was prepared by a procedure similar to thatdescribed in Preparation 1-(2) or 4-(2).

N-(3-Chlorophenyl)-2-(phthalimidoxy)acetamide.

I.R. (Nujol): 3370, 1795, 1745, 1675 cm⁻¹.

N.M.R. (DMSO-d₆, δ) 4.87 (2H, s), 7.0-7.8 (4H, m), 7.93 (4H, s).

(2) The following compound was prepared by a procedure similar to thatdescribed in Preparation 1-(3), 2-(3), 3-(2) or 4-(3).

N-(3-Chlorophenul)-2-(aminooxy)acetamide, mp. 68°-73° C.

I.R. (Nujol): 3350, 3280, 1670, 1595 cm⁻¹.

N.M.R. (DMSO-d₆ +D₂ O, δ) 4.17 (2H, s), 7.0-8.0 (4H, m).

(3) The following compound was prepared by a procedure similar to thatdescribed in Preparation 1-(4), 2-(2), 3-(3) or 4-(4).

2-[N-(3-Chlorophenyl)carbamoylmethoxyimino]-2-(2-formamidothiazol-4-yl)aceticacid (syn isomer).

I.R. (Nujol): 3300, 3150, 3050, 1725, 1685, 1620 cm⁻¹.

N.M.R. (DMSO-d₆ +D₂ O, δ): 4.80 (2H, s), 7.0-8.0 (4H, m), 7.63 (1H, s),8.57 (1H, s).

Preparation 7

(1) The following compound was prepared by a procedure similar to thatdescribed in Preparation 1-(2) or 4-(2).

N-(2-Thiazolyl)-2-(phthalimidoxy)acetamide.

I.R. (Nujol): 1795, 1745, 1710 cm⁻¹.

N.M.R. (DMSO-d₆, δ) 4.92 (2H, s), 7.26 (1H, d, J=4 Hz), 7.50 (1H, d, J-4Hz), 7.86 (4H, s).

(2) The following compound was prepared by a procedure similar to thatdescribed in Preparation 1-(3), 2-(2), 3-(2) or 4-(3).

N-(2-Thiazonyl)-2-(aminooxy)acetamide.

I.R. (Nujol): 3350, 3300, 3200, 1700, 1580 cm⁻¹.

N.M.R. (DMSO-d₆ +D₂ O, δ): 4.34 (2H, s), 7.22 (1H, d, J=4 Hz), 7.50 (1H,d, J=4 Hz).

(3) The following compound was prepared by a procedure similar to thatdescribed in Preparation 1-(4), 2-(3), 3-(3) or 4-(4).

2-[N-(2-Thiazolyl)carbamoylmethoxyimino]-2-(2-formimidothiazol-4-yl)aceticacid (syn isomer).

I.R. (Nujol): 1700, 1670, 1580, 1560 cm⁻¹

N.M.R. (DMSO-d₆ +D₂ O, δ): 4.94 (2H, s), 7.26 (1H, d, J=4 Hz), 7.50 (1H,d, J=4 Hz), 7.60 (1H, s), 8.56 (1H, s).

Preparation 8

The following compound was prepared by a procedure similar to thatdescribed in Preparation 1-(4), 2-(3), 3-(3) or 4-(4).

2-[N-(2-Hydroxy-3,5-dichlorophenyl)carbamoylmethoxyimino]-2-(2-formamidothiazol-4-yl)aceticacid (syn isomer).

I.R. (Nujol): 3330, 1755, 1720, 1680, 1590, 1540 cm⁻¹.

N.M.R. (DMSO-d₆ +D₂ O, δ): 4.93 (2H, s), 7.28 (1H, d, J=3 Hz), 7.67 (1H,s), 8.00 (1H, d, J=3 Hz), 8.60 (1H, s).

Preparation 9 (1) Preparation of2-(2-aminoethoxyimino)-2-(2-formamidothiazol-4-yl)acetic acid (synisomer)

To a solution of 2-(2-formamidothiazol-4-yl)glyoxylic acid (5.5 g.) inethanol (100 ml. ) was added a solution of2-(aminooxy)ethylamine.dihydrochloride (4.1 g.) in water (50 ml.). Theresulting mixture was adjusted to pH 4 with an aqueous solution ofsodium bicarbonate and stirred for 3 hours at room temperature.

The reaction mixture was evaporated to a volume of 100 ml. and cooled.The resulting precipitates were collected by filtration, washedsuccessively with cold-water and ethanol to give the title compound (6.5g.), mp 213° to 214° C. (dec.).

I.R. (Nujol): 3500-2100, 1705, 1658, 1590 cm⁻¹.

N.M.R. (DMSO-d₆, δ): 8.58 (1H, s), 7.42 (1H, s), 4.5-3.92 (2H, m),3.25-2.67 (2H, m).

(2) Preparation of2-[2-(2-Hydroxy-5-chlorobenzamido)ethoxyimino]-2-(2-formamidothiazol-4-yl)aceticacid (syn isomer)

To a suspension of2-(2-aminoethoxyimino)-2-(2-formamido)thiazol-4-yl)acetic acid (synisomer) (5.10 g.) in methylene chloride (100 ml.) was added1,5-diazabicyclo[5,4,0]undecene-5 (7.2 g.) to give a solution andthereto was added trimethylsilylchloride (5.14 g.) followed by stirringfor an hour at 10° C. After bistrimethylsilyl)acetamide (21.7 g.) wasadded, the mixture was stirred for 5 minutes at 10° C. To thus obtainedhomogeneous solution was added a solution of 2-hydroxy-5-chlorobenzoylchloride (4.54 g.) in methylene chloride (20 ml.) at -15° to -5° C.followed by stirring for 2 hours at -5° to 5° C. and for an hour at roomtemperature. The reaction mixture was concentrated to dryness and to theresidue were added cold water and ethyl acetate. After the mixture wasadjusted to pH 8 with sodium bicarbonate, the aqueous layer wasseparated, washed with ethyl acetate, then adjusted to pH 2 with 10%hydrochloric acid, and extracted with ethyl acetate. The extract waswashed with water, dried over magnesium sulfate and then concentrated todryness. The residue was triturated with diethyl ether to give the titlecompound (4.1 g.).

I.R. (Nujol): 3400, 3220, 3090, 1745, 1681, 1642, 1600, 1557 cm⁻¹.

N.M.R. (DMSO-d₆ +D₂ o, δ): 8.60 (1H, s), 7.97 (1H, d, J=2 Hz), 7.60 (1H,s), 7.46 (1H, d, d, J=2, 9 Hz), 7.00 (1H, d, J=9 Hz), 4.35 (2H, t, J=6Hz), 3.72 (2H, t, J=6 Hz).

Preparation 10

(1) A mixture of 2-(2-formamidothiazol-4-yl)-glyoxylic acid (1.59 g.),tert-butyl N-aminooxyethylcarbamate (1.40 g.) and methanol (25 ml.) wasstirred at room temperature for 6 hours. After removal of methanol fromthe resultant solution under reduced pressure, the residue waspulverized with diethyl ether. The precipitates were collected byfiltration to give2-[2-(tert-butoxycarboxamido)ethoxyimino]-2-(2-formamidothiazol-4-yl)aceticacid (syn isomer) (2.20 g.).

I.R. ν_(max) ^(Nujol) : 3140, 1698, 1604 cm⁻¹.

N.M.R. δ(DMSO-d₆, ppm): 1.37 (9H, s), 3.20 (2H, m), 3.97 (2H, m), 6.73(1H, broad s), 7.33 (1H, s), 8.50 (1H, s).

(2) Vilsmeier reagent was prepared from N, N-dimethylformamide (0.98 g.)and phosphoryl chloride (2.05 g.) in ethyl acetate (6 ml.) in a usualmanner.2-[2-(tert-Butoxycarboxamido)ethyoxyimino]-2-(2-formamidothiazol-4-yl)aceticacid (syn isomer) (4.0 g.) was added to the stirred suspension of theVilsmeier reagent in ethyl acetate (26 ml.) under ice cooling.

The resulting mixture was added to a solution of7-amino-3-(1,3,4,-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid(3.7 g.) and trimethylsilylacetamide (8.7 g.) in tetrahydrofuran (37ml.) at -25° C. and the mixture was stirred for 30 minutes at -15° C.After addition of water (100 ml.) and tetrahydrofuran (40 ml.) to thereaction mixture, the organic layer was separated.

To the organic layer was added water (100 ml.) and then the mixture wasadjusted to pH 7.5 with sodium bicarbonate. The aqueous layer wasseparated and thereto was added tetrahydrofuran. The mixture wasadjusted to pH 3.0 with 10% hydrochloric acid. The organic layer wasseparated, washed with a saturated aqueous solution of sodium chloride,dried over magnesium sulfate and evaporated under reduced pressure togive7-[2-[2-(tert-butoxycarboxamido)ethyoxyimino]-2-(2-formamidothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (5.9 g.).

I.R. ν(Nujol) 3400-3100, 1780, 1680, 1540 cm⁻¹.

N.M.R. (DMSO-d₆, δ, ppm): 1.35 (9H, s), 2.95-3.53 (2H, m), 3.53-3.90(2H, m), 3.90-4.28 (2H, m) 4.45 (2H, q, J=14 Hz), 5.17 (1H, d, J=5 Hz),5.85 (1H, dd, J=5 and 8 Hz), 7.4 (1H, s), 8.52 (1H, s), 9.53 (1H, s),9.57 (1H, d, J=8 Hz), 12.6 (1H, broad s).

(3) A mixture of7-[2-[2-(tert-butoxycarboxamido)-ethoxyimino]-2-(2-formamidothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (5.8 g.) and formic acid (60 ml.) was stirred for 3hours at 40° C. The reaction mixture was evaporated under reducedpressure. The residue was pulverized in acetonitrile and then washedwith diethyl ether to give7-[2-(2-aminoethoxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylicacid formate (syn isomer) (4.4 g.).

N.M.R. (DMSO-d₆, δ, ppm): 3.23 (2H, m), 4.07-4.77 (4H, m), 5.08 (1H, d,J=5 Hz), 5.78 (1H, dd, J=5 and 8 Hz), 7.52 (1H, s), 8.53 (1H, s), 9.5(1H, s), 9.55 (1H, d, J=8 Hz), 3.52 (2H, m).

PREPARATION OF THE OBJECT COMPOUND Example 1 Preparation of7-[2-{N-(2-Hydroxy-5-chlorophenyl)-carbamoylmethoxyimino}-2-(2-formamidothiazol-4-yl)-acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer)

A mixture of N,N-dimethylformamide (10 ml.) and phosphorus oxychloride(0.507 g.) was warmed at 40° C. for 30 minutes and subsequently cooledto -10° C. and thereto was added2-[N-(2-hydroxy-5-chlorophenyl)carbamoylmethoxyimino]-2-(2-formamidothiazol-4-yl)aceticacid (syn isomer) (1.00 g.). The resulting mixture was stirred at -10°to -5° C. for 50 minutes. On the other hand, to a solution oftrimethylsilylacetamide (3.60 g.) in methylene chloride (15 ml.) wasadded7-amino-3-(1-methyl-1H-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylicacid (1.003 g.). To this solution was added the stirred mixture obtainedabove at -25° C. followed by stirring at -20° to -10° C. for 2 hours.After concentration of the reaction mixture, to the residue were added asaturated aqueous solution of sodium bicarbonate (25 ml.) and water (50ml.). The resulting mixture was washed with ethyl acetate and theretowas added ethyl acetate (100 ml.). The mixture was adjusted to pH 2 with10% hydrochloric acid and extracted with ethyl acetate. The extract waswashed with water, dried over magnesium sulfate, treated with activatedcharcoal and then concentrated. The residue was triturated with diethylether and the precipitates were collected by filtration and then washedwith diethyl ether to give a powder (1.0 g.), which was dissolved in asmall amount of a mixture of acetone and ethyl acetate. This solutionwas washed with water twice, dried over magnesium sulfate and thenconcentrate to a small volume. To the concentrate was added diethylether followed by stirring at room temperature overnight. Theprecipitates were collected by filtration, washed with diethyl ether anddried to give the title compund (0.63 g.).

I.R. (Nujol): 3250, 1780, 1680 cm⁻¹.

N.M.R. (DMSO-d₆ +D₂ O, δ): 3.7 (2H, broad s), 3.92 (3H, s), 4.3 (2H,broad s), 4.8 (2H, broad s), 5.18 (1H, d, J=5 Hz), 5.87 (1H, d, J=5 Hz),6.8-7.2 (2H, m), 7.57 (1H, s), 7.97 (1H, d, J=2 Hz), 8.53 (1H, s).

Example 2 Preparation of7-[2-(0,0-Diethylphosphono)-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer)

A mixture of N,N-dimethylformamide (1.09 g.) and phosphorus oxychloride(2.08 g.) was warmed for 30 minutes at 40° C. Dry methylene chloride (30ml.) was added thereto at -15° C. and then a mixture of2-(0,0-diethylphosphono)methoxyimino-2-(2-formamidothiazol-4-yl)aceticacid (syn isomer) (4.5 g.) and dry methylene chloride (40 ml.) was addedthereto at -10° C. The resulting mixture was stirred for an hour at -5°to -10° C. On the other hand, a mixture of7-amino-3-(1-methyl-1H-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylicacid (4.9 g.), trimethylsilylacetamide (10.6 g.) and dry methylenechloride (75 ml.) was stirred for 15 minutes at 35° to 40° C. to give aclear solution. To this solution was was added at -15° to -10° C. theabove-obtained methylene chloride solution, and the resulting mixturewas stirred for an hour at -5° to -10° C. and then for an hour at 5° C.The reaction mixture was evaporated, and cold water and sodiumbicarbonate were added to the residue. The solution was washed withethyl acetate. The aqueous layer was adjusted to pH 3 to 4 with 10%hydrochloric acid after addition of ethyl acetate. The mixture wasshaken and the ethyl acetate layer was separated. The aqueous layer wasfurther adjusted to pH 3 to 4 with 10% hydrochloric acid after additionof ethyl acetate and shaker. The ethyl acetate layer was combined withthe ethyl acetate layer separated before. The combined ethyl acetatesolution was washed with water, dried and evaporated. To the residue wasadded diethyl ether to give a powder which was washed with a smallamount of ethyl acetate to give a power of the title compound (4.6 g.).

I.R. (Nujol): 3200, 1790, 1730, 1690 cm⁻¹.

N.M.R. (DMSO-d₆, δ): 1.2 (6H, t, J=7 Hz), 3.67 (2H, broad s), 3.7-4.7(8H, s), 3.90 (3H, s), 5.13 (1H, d, J=5 Hz), 5.78 (1H, d, d, J=8, 5 Hz),7.43 (1H, s), 8.50 (1H, s).

Example 3 Preparation of7-[2-{2-(0,0-Diethylphosphono)ethoxyimino}-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer)

A mixture of phosphorus oxychloride (4.9 g.) and N,N-dimethylformamide(2.56 g.) was warmed for 30 minutes at 40° C. and thereto was added drymethylene chloride (50 ml.). To the mixture was added a mixture of2-[2-(0,0-diethylphosphone)ethoxyimino]-2-(2-formamidothiazol-4-yl)-aceticacid (syn isomer) (9.3 g.) in dry methylene chloride (50 ml.) over aperiod of 5 minutes with stirring at -5° to -10° C. and stirring wascontinued for 40 minutes at -10° C. On the other hand, a mixture of7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (10.72 g.) and trimethylsilylacetamide (31 g.) in methylenechloride (150 ml.) was stirred for 15 minutes at 35° to 40° C. and thencooled to -15° C. To the mixture was added the stirred solution obtainedabove at -15° C. followed by stirring for an hour at -10° to -5° C. andfor an additional 30 minutes at -5° to 0° C. After concentration of thereaction mixture, to the residue was added ethyl acetate (500 ml.) andice-cold water (200 ml.). The resulting mixture was shaken and the ethylacetate layer was separated, washed with water, dried and thenconcentrated. To the residue (15 g.) was added ethyl acetate followed bystirring overnight. The precipitates were collected by filtration togive a powder, to which was added a small amount of ethyl acetatefollowed by stirring. The precipitate was again collected by filtrationand dried to give a powder of the title compound (9.7 g.).

I.R. (Nujol): 1785, 1730, 1690 cm⁻¹.

N.M.R. (DMSO-d₆ +D₂ O, δ) 1.24 (6H, t, J=7 Hz], 2.0-2.6 (2H, m), 3.4-4.6(10H, m), 3.96 (3H, s), 5.20 (1H, d, J=5 Hz), 5.85 (1H, d, J=5 Hz), 7.50(1H, s), 8.54 (1H, s).

Example 4 Preparation of7-[2-{2-(0,0-Diethylphosphono)-ethoxyimino}-2-(2-formamidothiazol-4-yl)acetamido]-3-(2-benzothiazolyl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer)

A mixture of phosphorus oxychloride (1.397 g.) and N,N-dimethylformamide(0.73 g.) was added to methylene chloride (1 ml.) at below 40° C.followed by stirring for 30 minutes at 40° C. After addition ofmethylene chloride (20 ml.) and cooling to -11° C., to the mixture wasadded a mixture of2-[2-(0,0-diethylphosphono)ethoxyimino]-2-(2-formamidothiazol-4-yl)aceticacid (syn isomer) (2.65 g.) in methylene chloride (20 ml.) over a periodof 5 minutes with stirring at -11° to -8° C. and then stirring wascontinued for 40 minutes at -10° to -8° C. On the other hand, a mixtureof 7-amino-3-(2-benzothiazolyl)thiomethyl-3-cephem-4-carboxylic acid(2.65 g.) and trimethylsilylacetamide (10.1 g.) was dissolved inmethylene chloride (50 ml.). To this solution was at a time added thestirred mixture obtained above under cooling at -30° C. followed bystirring 1.5 hours at -10° to -8° C. After removal of the solvent fromthe reaction mixture, to the residue were added ethyl acetate and water.The ethyl acetate layer was washed with a diluted hydrochloric acid (pHabout 2) and then extracted with a saturated aqueous solution of sodiumbicarbonate. The extract was washed with ethyl acetate and thereto wasadded ethyl acetate. After the mixture was adjusted to pH about 2 with10% hydrochloric acid, the ethyl acetate layer was separated, washedsuccessively with water and an aqueous solution of sodium chloride,dried over magnesium sulfate, treated with activated charcoal and thenevaporated. The residue was triturated with diethyl ether and theprecipitates were collected by filtration and then dried to give thetitle compound (3.37 g.), mp. 132° to 150° C. (dec.)

I.R. (Nujol): 3200, 1790, 1690 cm⁻¹.

N.M.R. (DMSO-d₆, δ): 1.20 (6H, t, J=7 Hz), 2.0-2.6 (2H, m), 3.60, 3.88(2H, ABq, J=18 Hz), 3.9-5.0 (8H, m), 5.20 (1H, d, J=5 Hz), 5.85 (1H,d,d, J=5, 8 Hz), 7.50 (1H, s), 7.2-8.1 (4H, m), 8.52 (1H, s), 9.70 (1H,d, J=8 Hz).

EXAMPLE 5 Preparation of7-[2-[N-(3-Pyridyl)carbamoylmethoxyimino]-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

A mixture of phosphorus oxychloride (1.6 g.) and N,N-dimethylformamide(31 ml.) was warmed at 40° C. for 30 minutes followed by cooling to -10°C. To the mixture was added2-[N-(3-pyridyl)carbamoylmethoxyimino]-2-(2-formamidothiazol-4-yl)aceticacid (syn isomer) (3.1 g.) followed by stirring for an hour at -10° to-7° C. On the other hand, a mixture of7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (3.2 g.) and trimethylsilylacetamide (7 g.) in methylene chloride(60 ml.) was stirred for 30 minutes at room temperature and then cooledto -15° C. To the mixture was added the above obtained dimethylformamidemixture followed by stirring for 1.5 hours at -15° to -10° C. To thereaction mixture were added ice-cold water and sodium bicarbonate. Theaqueous layer (pH 7 to 8) was separated and washed with ethyl acetateand then thereto was added ethyl acetate. After the pH was adjusted to 3to 4 with 10% hydrochloric acid, the precipitates were collected andthen dissolved in an aqueous solution of sodium bicarbonate. Theresulting mixture was treated with activated charcoal and the aqueouslayer was separated and then adjusted to pH 3 to 4 with 10% hydrochloricacid.

The precipitates were collected by filtration and dried to give thetitle compound (2.0 g.).

I.R. (Nujol): 1780, 1680 cm⁻¹.

N.M.R. (DMSO-d₆ +D₂ O, δ): 3.7 (2H, broad s), 3.90 (3H, s), 4.30 (2H,broad s), 4.8 (2H, broad s), 5.20 (1H, d, J=4.5 Hz), 5.90 (1H, d, J=4.5Hz), 7.2-7.5 (1H, m), 7.57 (1H, s), 7.9-8.4 (2H, m), 8.53 (1H, s), 8.8(1H, broad s).

EXAMPLE 6

The following compounds were prepared by procedures similar to thosedescribed in Examples 1 to 5.

(1)7-[2-{N-(2-tert-Butoxycarbonylphenyl)-carbamoylmethoxyimino}-2-(2-formamidothiazol-4-yl)-acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 175° to 185° C. (dec.).

I.R. (Nujol): 3500-3100, 1790, 1700, 1540 cm⁻¹

N.M.R. (DMSO-d₅, δ): 9.38 (1H, broad d, J=9 Hz), 8.58 (1H, s), 8.6-7.1(5H, m), 6.00 (1H, d,d, J=5, 9 Hz), 5.25 (1H, d, J=5 Hz), 4.83 (2H, s),4.35 (2H, broad s), 3.97 (3H, s), 3.73 (2H, broad s), 1.47 (9H, s).

(2)7-[2-{N-(3-Chlorophenyl)carbamoylmethoxyimino}-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. (Nujol): 3300, 1785, 1690 cm⁻¹.

N.M.R. (DMSO-d₆, δ): 3.7 (2H, broad s), 3.93 (3H, s), 4.3 (2H, broad s),4.8 (2H, broad s), 5.20 (1H, d, J=4.5 Hz), 5.92 (1H, d,d, J=4.5, 8 Hz),7.0-8.0 (4H, m), 7.57 (1H, s), 8.53 (1H, s).

(3)7-[2-{N-(2-Thiazolyl)carbamoylmethoxyimino}-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer)

I.R. (Nujol): 3250, 1785, 1740, 1700, 1670 cm⁻¹.

N.M.R. (DMSO-d₆, δ): 3.7 (2H, broad s), 3.93 (3H, s), 4.3 (2H, broad s),4.9 (2H, broad s), 5.20 (1H, d, J=5 Hz), 5.90 (1H, d,d, J=5, 8 Hz), 7.25(1H, d, J=4 Hz), 7.50 (1H, d, J=4 Hz), 7.53 (1H, s), 8.53 (1H, s), 9.90(1H, d, J=8 Hz).

(4)7-[2-{N-(2-Hydroxy-3,5-dichlorophenyl)-carbamoylmethoxyimino}-2-(2-formamidothiazol-4-yl)-acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer)

(5)7-[2-{2-(2-Hydroxy-5-chlorobenzamido)-ethoxyimino}-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), powder.

I.R. (Nujol): 3220, 1797, 1697, 1650, 1595, 1535, 1470 cm⁻¹.

N.M.R. (DMSO-d₆ +D₂ O, δ): 8.53 (1H, s), 7.87 (1H, d, J=2 Hz), 7.47 (1H,s), 7.38 (1H, d,d, J=2, 9 Hz), 6.90 (1H, d, J=9 Hz), 5.85 (1H, d, J=5Hz), 5.12 (1H, d, J=5 Hz), 4.5-4.0 (4H, m), 3.92 (3H, s), 3.8-3.1 (4H,m).

(6)7-[2-{N-(2-Hydroxy-5-chlorophenyl)-carbamoylmethoxyimino}-2-(2-formamidothiazol-4-yl)-acetamido]-cephalosporanicacid (syn isomer), mp. 170° to 190° C. (dec. with changing color).

I.R. (Nujol):

3250, 1785, 1740, 1670 cm⁻¹.

N.M.R. (DMSO-d₆ +D₂ O, δ): 2.02 (3H, s), 3.46, 3.65 (2H, ABq, J=17 Hz),4.77, 5.02 (2H, ABq, J=13 Hz), 4.85 (2H, s), 5.22 (1H, d, J=5 Hz), 5.91(1H, d, J=5 Hz), 6.85-7.15 (2H, m), 7.57 (1H, s), 8.00 (1H, d, J=2 Hz),8.54 (1H, s).

(7)7-[2-{N-(3-Chlorophenyl)carbamoylmethoxyimino}-2-(2-formamidothiazol-4-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 160° C. (dec.).

I.R. (Nujol): 3300, 1785, 1680 cm⁻¹.

N.M.R. (DMSO-d₆ +D₂ O, δ): 2.72 (3H, s), 3.75 (2H, broad s), 4.30, 4.57(2H, ABq, J=14 Hz), 4.83 (2H, broad s), 5.27 (1H, d, J=5 Hz), 6.00 (1H,d, J=5 Hz), 7.0-8.0 (5H, m), 8.58 (1H, s).

(8)7-[2-{N-(2-Hydroxy-5-chlorophenyl)carbamoylmethoxyimino}-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 165° to 175° C. (dec.).

(9)7-[2-Phosphonomethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 210° to 220° C. (dec.).

(10)7-[2-{2-(O,O-Diethylphosphono)ethoxyimino}-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid.hydrochloride (syn isomer), mp. 170° to 180° C. (dec.).

(11)7-[2-(2-Phosphonoethoxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 180° to 210° C. (dec.).

(12)7-[2-(2-Phosphonoethoxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-(2-benzothiazol)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 170° to 210° C. (dec.).

(13)7-[2-{N-(3-Pyridyl)carbamoylmethoxyimino}-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), powder, mp. 180° to 210° C. (dec.).

(14)7-[2-{N-(2-Carboxyphenyl)carbamoylmethoxyimino}-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 220° to 230° C. (dec.).

(15)7-[2-{N-(3-Chlorophenyl)carbamoylmethoxyimino}-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 191° C. to 195° C. (dec.).

(16)7-[2-{N-(2-Thiazolyl)carbamoylmethoxyimino}-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 180° C. to 185° C. (dec.).

(17)7-[2-{N-(2-Hydroxy-3,5-dichlorophenyl)-carbamoylmethoxyimino}-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 161° to 170° C. (dec.).

(18)7-[2-{2-(2-Hydroxy-5-chlorobenzamido)-ethoxyimino}-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 220° C. to 230° C. (dec.).

(19)7-[2-{N-(2-Hydroxy-5-chlorophenyl)-carbamoylmethoxyimino}-2-(2-aminothiazol-4-yl)acetamido]-cephalosporanicacid (syn isomer), mp.>250° C.

(20)7-[2-{N-(3-Chloropheyl)carbamoylmethoxyimino}-2-(2-aminothiazol-4-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 173° C. (dec.).

(21)7-[2-[2-[{3-(2-Chloropheyl)-5-methylisoxazol-4-yl}carboxamino]ethoxyimino]-2-(2-formamidothiazol-4-yl)-acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. (Nujol): 3400-3100, 1780, 1660, 1540 cm⁻¹.

(22)7-[2-[2-[{3-(2-Chlorophenyl)-5-methylisoxazol-4-yl}carboxyamido]ethoxyimino]-2-(2-aminothiazol-4-yl)-acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. (Nujol): 3400-3100, 1770, 1650, 1520 cm⁻¹.

EXAMPLE 7 Preparation of7-[2-{N-(2-Hydroxy-5-chlorophenyl)-carbamoylmethoxyimino}-2-(2-aminothiazol-4-yl)-acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

To a mixture of acetone (1 ml.), methanol (4 ml.) and7-[2-{N-(2-hydroxy-5-chlorophenyl)carbamoylmethoxyimino}-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (0.55 g.) was added conc. hydrochloric acid (0.11 ml.)followed by stirring for 3 hours at room temperature. The reactionmixture was concentrated and then to the residue were added water (3ml.) and an aqueous solution of sodium bicarbonate whereby the pH wasadjusted to about 2. The resulting mixture was stirred at roomtemperature and the precipitates were collected by filtration, washedwith water and then dried to give the title compound (0.40 g.), mp. 165°to 175° C. (dec.)

I.R. (Nujol): 3300, 3200, 1780, 1680, 1640, 1610 cm⁻¹.

N.M.R. (DMSO-d₆ +D₂ O, δ): 3.7 (2H, broad s), 3.90 (3H, s), 4.3 (2H,broad s), 4.8 (2H, broad s), 5.14 (1H, d, J=5 Hz), 5.80 (1H, d, J=5 Hz),6.7-7.1 (3H, m), 8.0 (1H, broad s)

EXAMPLE 8 Preparation of7-[2-Phosphonomethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

A mixture of7-[2-(O,O-diethylphosphono)-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-cargoxylicacid (syn isomer) (4.3 g.), methylene chloride (65 ml.) andbis(trimethylsilyl)acetamide (6.5 g.) was stirred for 30 minutes at roomtemperature and thereto was added trimethylsilylbromide (4.85 g.) over aperiod of 15 minutes with stirring at about 20° C. and then the stirringwas continued for an additional 4 hours at room temperature. Thereaction mixture containing7-[2-phosphonomethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) was concentrated and then to the residue was addedmethanol (65 ml.) under cooling followed by addition of conc.hydrochloric acid (2 ml.) with stirring. The resulting mixture wasstirred for 1.5 hours at room temperature and concentrated. To theresidue was added water (150 ml.) and the mixture was washed with ethylacetate twice. The aqueous layer was adjusted to pH 2 to 3, with sodiumbicarbonate and subjected to column chromatography (non-ion adsorptionresin, Diaion HP20 prepared by Mitsubishi Chemical Industries) (150 ml.)and the column was washed with water and then eluted successively with10% methanol (1 l.), 20% methanol (1 l.) and 30% methanol (3 l.). Thefractions containing the desired compound were evaporated to give thetitle compound (2.6 g.) mp. 210° to 220° C. (dec.).

I.R. (Nujol): 1770, 1650 cm⁻¹

N.M.R. (DMSO-d₆ +D₂ O, δ): 3.7 (2H, broad s), 3.94 (3H, s), 4.3 (4H,broad s), 5.14 (1H, d, J=5 Hz), 5.76 (1H, d, J=5 Hz), 6.80 (1H, s).

EXAMPLE 9 Preparation of7-[2-{2-(O,O-diethylphosphono)ethoxyimino}-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1-H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid hydrochloride (syn isomer)

To a mixture of7-[2-{2-(O,O-diethylphosphono)ethoxyimino}-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (0.9 g.) and methanol (10 ml.) was added conc.hydrochloric acid (0.2 ml.) followed by stirring for 2.5 hours at roomtemperature. The reaction mixture was concentrated and to the residuewas added ethyl acetate followed by stirring. The precipitates werecollected by filtration to give the title compound (0.85 g.), mp. 170°to 180° C. (dec.).

I.R. (Nujol): 1780, 1720, 1680, 1630 cm⁻¹.

N.M.R. (DMSO-d₆, δ): 1.23 (6H, t, J=7 Hz), 1.9-2.5 (2H, m), 4.00 (3H,s), 3.5-4.8 (10H, m), 5.23 (1H, d, J=4.5 Hz), 5.83 (1H, d,d, J=4.5, 8Hz), 7.10 (1H, s), 9.93 (1H, d, J-8 Hz).

EXAMPLE 10 Preparation of7-[2-(2-Phosphonoethoxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

A mixture of7-[2-{2-(O,O-diethylphosphono)-ethoxyimino}-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (6.2 g.) methylene chloride (90 ml.) andbis(trimethylsiilyl)acetamide (9.2 g.) was stirred for 30 minutes atroom temperature and thereto was added trimethylsilyl bromide (6.9 g.)over a period of 30 minutes with stirring at 20° to 25° C. and thenstirring was continued for 5 hours at 25° to 27° C. The reaction mixturecontaining7-[2-(2-phosphonethoxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) was concentrated and to the residue were added coldmethanol (100 ml.) and cold conc. hydrochloric acid (4 ml.) followed bystirring for an hour at room temperature and a further addition of conc.hydrochloric acid (2 ml.). The resulting mixture was stirred for an hourat room temperature and then concentrated. To the residue was addedwater (300 ml.) and the mixture was adjusted to pH 2 to 3 with sodiumbicarbonate and then subjected to column chromatography (non-ionadsorption resin, Diaion HP 20 prepared by Mitsubishi ChemicalIndustries) (200 ml.). The column was washed with water (1 l.) and theneluted successively with 10% methanol (1 l.), 20% methanol (1 l.), 30%methanol (1 l.) and 40% methanol (2 l.). The fractions containing thedesired compound were evaporated to give the title compound (3.7 g.),mp. 180° to 210° C. (dec.)

I.R. (Nujol): 3300, 1780, 1670, 1640 cm⁻¹.

N.M.R. (DMSO-d₆ +D₂ O, δ): 1.7-2.4 (2H, m), 3.7 (2H, broad s), 3.92 (3H,s), 4.0-4.6 (4H, m), 5.10 (1H, d, J=5 Hz), 5.77 (1H, d, J=5 Hz), 6.77(1H, s).

EXAMPLE 11 Preparation of7-[2-(2-Phosphonoethoxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-(2-benzothiazolyl)-thiomethyl-3-cephem-4-carboxylicacid (syn isomer)

A mixture of7-[2-{2-(O,O-diethylphosphono)-ethoxyimino}-2-(2-formamidothiazol-4-yl)acetamido]-3-(2-benzothiazolyl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (2.59 g.), methylene chloride (30 ml.) andbis(trimethylsilyl)acetamide (2.14 g.) was stirred for 30 minutes at 18°to 20° C. and thereto was added trimethylsilyl bromide (2.68 g.)followed by stirring for 5 hours and 45 minutes at 19° to 21° C. Thereaction mixture containing7-[2-(2-phosphonoethoxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-(2-benzothiazolyl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) was concentrated and to the residue were addedmethanol (30 ml.) and conc. hydrochloric acid (3 ml.). The mixture wasstirred for 1.5 hours at room temperature and then evaporated. Theresidue was dissolved in an aqueous solution of sodium bicarbonate andthe solution was washed with ethyl acetate and then adjusted to pH about2 with 10% hydrochloric acid. The precipitates were collected byfiltration under cooling, washed with water, dried under reducedpressure and then suspended in methanol (20 ml.). After conc.hydrochloric acid was added to the suspension to dissolve theprecipitates, the resulting solution was treated with activated charcoaland then thereto was added dropwise a mixture of conc. ammonia water andmethanol (1:5) whereby the pH was adjusted to 3 to 4. The precipitateswere collected by filtration under cooling to give a powder of the titlecompound (0.85 g.), mp. 170° to 210° C.

I.R. (Nujol): 1780, 1680, 1630 cm⁻¹.

N.M.R. (73° C., D₂ O+NaHCO₃, δ): 1.9-2.4 (2H, m), 5.16 (1H, d, J=5 Hz),5.84 (1H, d, J=5 Hz), 6.92 (1H, s), 7.0-7.9 (4H, m).

EXAMPLE 12 Preparation of7-[2-{N-(3-Pyridyl)carbamoylmethoxyinino}-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer)

To a suspension of7-[2-{N-(3-pyridyl)carbamoylmethoxyimino}-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (2.7 g.) in methanol (40 ml.) was added conc.hydrochloric acid (1.09 ml.) with stirring at room temperature followedby stirring for 2 hours at the same temperature. The reaction mixturewas separated by decantation into two groups, that is, a methanol layerand viscous precipitates. The methanol layer was treated with activatedcharcoal and concentrated and then the residue was dissolved in water.After the solution was adjusted to pH 3 to 4 with an aqueous solution ofsodium bicarbonate, the precipitates are collected by filtration to givea powder of the title compound (0.6 g.). On the other hand, the viscousprecipitates were dissolved in a mixture of methanol conc. hydrochloricacid and water and the solution was stirred for an hour at roomtemperature, treated with activated charcoal and then concentrated. Theresidue was dissolved in water and thereto was added an aqueous solutionof sodium bicarbonate under cooling whereby the pH was adjusted to 3 to4. The precipitates were collected by filtration to give a powder of thetitle compound (1.0 g.). Total yield: 1.6 g. mp. 180° to 210° C.

I.R. (Nujol): 3340, 3230, 1770, 1677, 1623, 1540 cm⁻¹.

N.M.R. (DMSO-d₆ +D₂ O, δ): 3.7 (broad s), 3.97 (3H, s), 4.3 (2H, broads), 4.8 (2H, broad s), 5.20 (1H, d, J=5 Hz), 5.90 (1H, d, J=5 Hz), 6.97(1H, s), 7.47 (1H, d,d, J=8, 4 Hz), 8.0-8.5 (2H, m), 8.85 (1H, d, J=2Hz).

EXAMPLE 13 Preparation of7-[2-{N-(2-Carboxyphenyl)carbamoylmethoxyimino}-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer)

7-[2-{N-(2-tert-Butoxycarbonylphenyl)carbamoylmethoxyimino}-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (2.0 g.) was added to a mixture of trifluoroaceticacid (7 ml.) and anisole (0.35 ml.) with stirring at about 10° C.,followed by stirring for 1.5 hours at 5° to 10° C. and for an additional15 minutes at room temperature. After concentration of the reactionmixture, to the residue were added methanol (30 ml.) and conc.hydrochloric acid (2.33 ml.). The resulting mixture was stirred for 1.5hours at room temperature and concentrated and then the residue wasshaken with a mixture of an aqueous solution of sodium bicarbonate andethyl acetate. The aqueous layer (pH 7 to 8) was separated and theretowas added ethyl acetate and 10% hydrochloric acid with stirring wherebythe pH was adjusted to 2 to 3. The resulting precipitates were filteredand redissolved in an aqueous solution of sodium bicarbonate. To theaqueous solution (150 ml.) was added ethyl acetate (300 ml.) and themixture was acidified to pH 2 to 3 with 10% hydrochloric acid. The ethylacetate layer was separated, washed with an aqueous solution of sodiumchloride, dried and then concentrated. The residue was washed withdiethyl ether to give the title compound (0.8 g.). mp. 220° to 230° C.(dec.)

I.R. (Nujol): 3400-3100, 1782, 1680, 1538 cm⁻¹.

N.M.R. (DMSO-d₆ +D₂ O, δ): 8.54 (1H, d, J=8 Hz), 7.99 (1H, d, J=8 Hz),7.62 (1H, t, J=8 Hz), 7.20 (1H, t, J=8 Hz), 6.91 (1H, s), 5.89 (1H, d,J=5 Hz), 5.16 (1H, d, J=5 Hz), 4.74 (2H, s), 4.37, 4.22 (2H, ABq, J=13Hz), 3.94 (3H, s), 3.75, 3.60 (2H, ABq, J=17 Hz).

Example 14

The following compounds were prepared by procedures similar to thosedescribed in Examples 7 to 13.

(1)7-[2-{N-(3-Chlorophenyl)carbamoylmethoxyimino}-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 191° to 195° C. (dec.)

I.R. (Nujol): 3300, 3200, 1775, 1680 cm⁻¹.

N.M.R. (DMSO-d₆ +D₂ O, δ): 3.7 (2H, broad s), 3.90 (3H, s), 4.3 (2H,broad s), 4.7 (2H, broad s), 5.15 (1H, d, J=5 Hz), 5.83 (1H, d, J=5 Hz),6.93 (1H, s), 7.0-7.9 (4H, m).

(2)7-[2-{N-(2-Thiazolyl)carbamoylmethoxyimino}-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 180° to 185° C. (dec.)

I.R. (Nujol): 3330, 3230, 1780, 1680, 1630, 1550 cm⁻¹.

N.M.R. (DMSO-d₆, δ): 3.74, 3.64 (2H, ABq, J=18 Hz), 3.95 (3H, s), 4.26,4.35 (2H, ABq, J=14 Hz), 4.85 (2H, s), 5.18 (1H, d, J=5 Hz), 5.84 (1H,d,d, J=8, 5 Hz), 6.88 (1H, s), 7.26 (1H, d, J=3 Hz), 7.50 (1H, d, J=3Hz), 9.80 (1H, d, J=8 Hz).

(3)7-[2-{N-(2-Hydroxy-3,5-dichlorophenyl)carbamoylmethoxyimino}-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 161° to 170° C. (dec.).

I.R. (Nujol): 3300, 3200, 1775, 1675 cm⁻¹.

N.M.R. (DMSO-d₆, δ): 3.56, 3.76 (2H, ABq, J=18 Hz), 3.90 (3H, s), 4.20,4.38 (2H, ABq, J=14 Hz), 4.73 (2H, s), 5.14 (1H, d, J=5 Hz), 5.80 (1H,d,d, J=8, 5 Hz), 6.84 (1H, s), 7.24 (1H, d, J=2 Hz), 7.80 (1H, d, J=2Hz).

(4)7-[2-{2-(2-Hydroxy-5-chlorobenzamido)ethoxyimino}-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 220° to 230° C. (dec.).

I.R. (Nujol): 3330, 1789, 1678, 1640, 1595, 1540 cm⁻¹.

N.M.R. (DMSO-d₆, δ): 9.56 (1H, d, J=9 Hz), 8.90 (1H, broad s), 7.91 (1H,d, J=2 Hz), 7.44 (1H, d,d, J=9, 2 Hz), 6.96 (1H, d, J=9 Hz), 6.82 (1H,s), 5.85 (1H, d,d, J=8, 5 Hz), 5.13 (1H, d, J=5 Hz), 4.6-4.0 (4H, m),3.93 (3H, s), 3.1-3.9 (4H, m).

(5)7-[2-{N-(2-Hydroxy-5-chlorophenyl)carbamoylmethoxyimino}-2-(2-aminothiazol-4-yl)acetamido]cephalosporanicacid (syn isomer), mp>250° C.

I.R. (Nujol): 3330, 1777, 1738, 1670 cm⁻¹.

N.M.R. (DMSO-d₆ +D₂ O, δ) 2.03 (3H, s), 3.45, 3.62 (2H, ABq, J=14 Hz),4.72, 4.97 (2H, ABq, J=14 Hz), 5.17 (1H, d, J=5 Hz), 5.87 (1H, d, J=5Hz), 6.6-7.1 (3H, m), 8.00 (1H, d, J=2 Hz).

(6)7-[2-{N-(3-Chlorophenyl)carbamoylmethoxyimino}-2-(2-aminothiazol-4-yl)acetamide]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 173° C. (dec.).

I.R. (Nujol): 3320, 1767, 1675 cm⁻¹.

N.M.R. (DMSO-d₆ +D₂ O, δ): 2.70 (3H, s), 3.60, 3.77 (2H, ABq, J=18 Hz),4.22, 4.48 (2H, ABq, J=14 Hz), 4.77 (2H, broad s), 5.20 (1H, d, J=5 Hz),5.88 (1H, d, J=5 Hz), 6.93 (1H, s), 7.0-7.9 (4H, m).

(7)7-[2-[2-[{3-(2-Chlorophenyl)-5-methylisoxazol-4-yl}carboxamido]ethoxyimino]-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. (Nujol): 3400-3100, 1770, 1650, 1520 cm⁻¹.

N.M.R. (DMSO-d₆, δ): 3.17-3.87 (4H, m), 4.1 (2H, m), 4.45 (2H, q, J=14Hz), 5.17 (1H, d, J=5 Hz), 5.80 (1H, d d, J=5.8 Hz), 6.80 (1H, s), 7.55(4H, s), 9.50 (1H, d, J=8 Hz), 9.56 (1H, s).

Example 15 Preparation of7-[2-{N-(2-Hydroxy-5-chlorophenyl)carbamoylmethoxyimino}-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer)

To a mixture of7-[2-{N-(2-hydroxy-5-chlorophenyl)carbamoylmethoxyimino}-2-(2-formamidothiazol-4-yl)acetamido]cephalosporanicacid (syn isomer) (653 mg.), 1-methyl-1H-tetrazol-5-thiol (140 mg.) andsodium bicarbonate (190 mg.) in phosphate buffer (pH 6.4) (50 ml.) wasstirred for 5 hours at 60° to 65° C. After cooling, the reaction mixturewas washed with ethyl acetate and then thereto was added ethyl acetate.The mixture was adjusted to pH 2 with 10% hydrochloric acid and theethyl acetate layer was separated, washed with water, dried overmagnesium sulfate and then evaporated. The residue was pulverized withdiethyl ether, washed with diethyl ether, collected by filtration andthen dried to give the title compound (350 mg.).

I.R. (Nujol): 3250, 1780, 1680 cm⁻¹.

N.M.R. (DMSO-d₆ +D₂ O, δ): 3.7 (2H, broad s), 3.92 (3H, s), 4.3 (2H,broad s), 4.8 (2H, broad s), 5.18 (1H, d, J=5 Hz), 5.87 (1H, d, J=5 Hz),6.8-7.2 (2H, m), 7.57 (1H, s), 7.97 (1H, d, J=2 Hz), 8.53 (1H, s).

Example 16

The following compounds were prepared by a procedure similar to thatdescribed in Example 15.

(1)7-[2-(O,O-Diethylphosphono(methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. (Nujol): 3200, 1790, 1730, 1690 cm⁻¹.

(2)7-[2-{2-(O,O-Diethylphosphono)ethoxyimino}-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. (Nujol): 1785, 1730, 1690 cm⁻¹.

(3)7-[2-{2-(O,O-Diethylphosphono)ethoxyimino}-2-(2-formamidothiazol-4-yl)acetamido]-3-(2-benzothiazolyl)-thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 132° to 150° C. (dec.).

(4)7-[2-{N-(3-Pyridyl)carbamoylmethoxyimino}-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. (Nujol): 1780, 1680 cm⁻¹.

(5)7-[2-{N-(2-tert-Butoxycarbonylphenyl)carbamoylmethoxyimino}-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 175° to 185° C. (dec.)

(6)7-[2-{N-(3-Chlorophenyl)carbamoylmethoxyimino}-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. (Nujol): 3300, 1785, 1690 cm⁻¹.

(7)7-[2-{N-(2-Thiazolyl)carbamoylmethoxyimino}-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. (Nujol): 3250, 1785, 1740, 1700, 1670 cm⁻¹.

(8)7-[2-{N-(2-Hydroxy-3,5-dichlorophenyl)carbamoylmethoxyimino}-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

(9)7-[2-{2-(2-Hydroxy-5-chlorobenzamido)ethoxyimino}-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), powder.

I.R. (Nujol): 3220, 1797, 1697, 1650, 1595, 1535, 1470 cm⁻¹.

(10)7-[2-{N-(3-Chlorophenyl)carbamoylmethoxyimino}-2-(2-formamidothiazol-4-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 160° C. (dec.)

(11)7-[2-{N-(2-Hydroxy-5-chlorophenyl)carbamoylmethoxyimino}-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 165° to 175° C. (dec.).

(12)7-[2-Phosphonomethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 210° to 220° C. (dec.).

(13)7-[2-{2-(O,O-Diethylphosphono)ethoxyimino}-2-(2-amonothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid. hydrochloride (syn isomer), mp 170° to 180° C. (dec.).

(14)7-[2-(2-Phosphonoethoxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 180° to 210° C. (dec.).

(15)7-[2-(2-Phosphonoethoxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-(2-benzothiazolyl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 170° to 210° C. (dec.).

(16)7-[2-{N-(3-Pyridyl)carbamoylmethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), powder, mp. 180° to 210° C. (dec.).

(17)7-[2-{N-(2-Carboxyphenyl)carbamoylmethoxyimino}-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 220° to 230° C. (dec.).

(18)7-[2-{N-(3-Chlorophenyl)carbamoylmethoxyimino}-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 191° to 195° C. (dec.).

(19)7-[2-{N-(2-Thiazolyl)carbamoylmethoxyimino}-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 180° to 185° C. (dec.).

(20)7-[2-{N-(2-Hydroxy-3,5-dichlorophenyl)carbamoylmethoxyimino}-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 161° to 170° C. (dec.).

(21)7-[2-{2-(2-Hydroxy-5-chlorobenzamido)-ethoxyimino}-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 220° to 230° C. (dec.).

(22)7-[2-{N-(3-Chlorophenyl)carbamoylmethoxyimino}-2-(2-aminothiazol-4-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 173° C. (dec.).

(23)7-[2-[2-[{3-(2-Chlorophenyl)-5-methylisoxazol-4-yl}carboxamido]ethoxyimino]-2-(2-formamidothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. (Nujol): 3400-3100, 1780, 1660, 1540 cm⁻¹.

(24)7-[2-[2-[{3-(2-Chlorophenyl)-5-methylisoxazol-4-yl}carboxamido]ethoxyimino]-2-(2-aminothiazol-4-yl)-acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. (Nujol): 3400-3100, 1770, 1650, 1520 cm⁻¹.

Example 17

A solution of7-[2-(2-aminoethoxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid formate (syn isomer) (0.5 g.) and bis(trimethylsilyl)acetamido (1.5g.) in dry tetrahydrofuran (10 ml) was stirred at 0° to 5° C. andthereto was added 3-(2-chlorophenyl)-5-methylisoxazole-4-carbonylchloride (0.23 g.) The resulting mixture was stirred for 5 hours at 0°to 5° C. After the addition of water (20 ml) and ethyl acetate (20 ml)to the reaction mixture, the organic layer was separated. The organiclayer was washed with a saturated aqueous solution of sodium chloride,dried over magnesium sulfate and then evaporated under reduced pressureto give7-[2-[2-[{3-(2-chlorophenyl)-5-methylisoxazol-4-yl}carboxamido]ethoxyimino]-2-(2-formamidothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (0.4 g.)

I.R. (Nujol): 3400-3100, 1780, 1660, 1540 cm⁻¹.

N.M.R. (DMSO-d₆, δ): 2.43 (3H, s), 3.17-3.73 (4H, m), 4.07 (2H, m), 4.42(1H, q, J=13 Hz), 5.12 (1H, d, J=5 Hz), 5.78 (1H, dd, J=5 and 8 Hz),7.38 (1H, s), 7.45 (4H, s), 8.47 (1H, s), 9.48 (1H, s), 9.52 (1H, d, J=8Hz), 12.5 (1H, broad s).

What we claim is:
 1. A compound of the formula: ##STR13## wherein R¹ isamino or lower alkanoylamino;R² is --CONH--R⁵ or --NHCO--R^(5') R⁵ isphenyl having one halogen, one carboxy or one lower alkoxycarbonyl,phenyl having one halogen and one hydroxy, or phenyl having two halogensand one hydroxy; R^(5') is phenyl having one halogen and one hydroxy;and A is methylene or ethylene;or a pharmaceutically acceptable saltthereof.
 2. The compound of claim 1, which is2-[N-(2-Hydroxy-5-chlorophenyl)carbamoylmethoxyimino]-2-(2-formamidothiazol-4-yl)aceticacid (syn isomer).
 3. The compound of claim 1, which is2-[N-(2-tert-Butoxycarbonylphenyl)carbamoylmethoxyimino]-2-(2-formamidothiazol-4-yl)aceticacid (syn isomer).
 4. The compound of claim 1, which is2-[N-(3-Chlorophenyl)carbamoylmethoxyimino]-2-(2-formamidothiazol-4-yl)aceticacid (syn isomer).
 5. The compound of claim 1, which is2-[N-(2-Hydroxy-3,5-dichlorophenyl)carbamoylmethoxyimino]-2-(2-formamidothiazol-4-yl)aceticacid (syn isomer).
 6. The compound of claim 1, which is2-[2-(2-Hydroxy-5-chlorobenzamido)ethoxyimino]-2-(2-formamidothiazol-4-yl)aceticacid (syn isomer).